Heterocyclic compounds and their use for treatment of helminthic infections and diseases

ABSTRACT

Provided herein are Heterocyclic compounds of formula I: 
     
       
         
         
             
             
         
       
         
         
           
             and pharmaceutically acceptable salts, tautomers, isotopologues, or stereoisomers thereof, wherein W, X, Y, R 1 , R 2 , and R N  are as defined herein, compositions comprising an effective amount of a Heterocyclic Compound, and methods for treating or preventing animal and human filarial worm infections and diseases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.62/839,552 filed Apr. 26, 2019 the disclosure of which is incorporatedherein by reference in its entirety.

FIELD

Disclosed herein are compounds and methods for the prevention and/ortreatment of helminthic infections and diseases caused by helminthicinfection. Also provided herein are such compounds for use in suchmethods. Also disclosed herein are pharmaceutical compositionscomprising such compounds for use in such methods of preventing ortreating helminthic infection and/or diseases associated with helminthicinfection.

BACKGROUND

There are several types of parasitic worms (helminths), with the mostcommon worldwide the intestinal nematodes or soil-transmitted helminths(STH), schistosomes (parasites of schistosomiasis) and filarial worms,which cause lymphatic filariasis (LF) and onchocerciasis. Filariasis isa parasitic disease that is caused by thread-like filarial nematodes orroundworms. Filariasis is a vector-borne disease that is transmitted viainsect bites. Infective larvae of the nematodes can be introduced intothe human body via bites of blood sucking insects like mosquitoes orflies. Filariasis can also affect domestic animals like dogs. In dogs,dirofilariasis which is also called heartworm disease, is caused bynematodes called Dirofilaria immitis and Dirofilaria repens.Dirofilariasis is considered endemic in 49 states of the United States.The vectors as well are blood sucking insects like mosquitoes.

The major causes of human filariasis are the filarial nematodesWuchereria bancrofti, Brugia malayi, Brugia timori, Onchocerca volvulusand Mansonella species that have human hosts. The nematodes Wuchereriabancrofti, Brugia malayi and Onchocerca volvulus are responsible formost of the debilitating filarial infections in more than 80 developingcountries of the tropics and sub-tropics where 1.1 billion are at riskof infection and about 150 million are infected. All three species are asource of severe pathologies that result in high morbidity and increasedmortality. The infection can cause severe morbidity in up to 50% ofthose infected with the nematodes.

W. bancrofti and B. malayi infections can develop into lymphaticfilariasis, often seen as hydrocoele in men and/or lymphoedema and inextreme cases elephantiasis. O. volvulus infections can develop intosevere dermatitis and/or onchocerciasis, the visual impairment givingthe latter disease its common name River Blindness. Community directedmass drug administration programs are designed to control theseinfections and eliminate them as a public health problem.

Current efforts aim to eliminate these parasitic nematodes through theuse of drugs like diethylcarbamazine, ivermectin, and albendazole thatkill the larvae, but not the adult worms. The antihelmintic drugdiethylcarbamazine is used to combat lymphatic filariasis in countrieswithout co-endemic O. volvulus infections, i.e. outside of Africa.Ivermectin is used to combat onchocerciasis. The greatest efficacy ofboth drugs is against the first stage larvae found in the blood streamor in the dermis. Since the worms can live up to 14 years and are fecundfor most of their lifespan, populations in endemic regions must betreated with high coverage (at least 65%) for many years to breaktransmission of the disease to uninfected persons.

Two of the major constraints of treatment of filarial diseases are (i)the absence of a macrofilaricidal drug (or for onchocerciasis, one whichpermanently sterilizes the worm) and (ii) the risk of worms developingdrug-resistance. For example, currently available treatments foronchocerciasis include ivermectin, which kills worm larvae, but haslittle or no activity against adult Onchocerca volvulus parasites. Thus,infected patients must be retreated with ivermectin for several yearsuntil the adult worms die naturally. In addition, there are alsopotential signs of resistance to ivermectin within the parasite in a fewareas. Osei-Atweneboana M Y, et al., Phenotypic Evidence of EmergingIvermectin Resistance in Onchocerca volvulus, PLoS Negl Trop Dis 5(3):e998 (2011). In addition, there is a danger in treating patientsco-infected with both (i) Wuchereria bancrofti, Brugia malayi, Brugiatimori, and/or Onchocerca volvulus; and (ii) Loa loa with ivermectin. Insuch co-infected patients, ivermectin treatment can cause severereactions, including encephalopathy, leading to coma or even death.

Heartworm infection, caused by the endoparasite Dirofilaria immitis (D.immitis), can be a severe and life-threatening disease in animals suchas dogs and cats. Heartworm has a complicated life cycle involvingseveral life stages before they mature into adults that will eventuallyinfect the pulmonary artery of the host animal. Heartworm transmissionalso requires the mosquito to act as an intermediate host to completethis life cycle. For example, the beginning of the heartworm life cycleand transmission process involves a mosquito biting a previouslyinfected dog and ingesting blood containing heartworm microfilariae(larva stage 1). Within the mosquito, the microfilariae will molt intoinfective larva stage 3 (L3) worms over a two week period. Once themosquito bites another dog, infective L3 worms will move through thebite wound to enter the host and migrate into the tissues where theywill begin molting into larva stage 4 (L4) worms, usually within 1 to 3days post infection. Subsequently, L4 worms will continue theirmigration through tissues and molt into sexually immature or“adolescent” adults (larva stage 5, immature adult), approximately 50-70days post infection. Sexually mature worms will eventually migrate tothe heart and lungs of the dog, as early as 70 days post infection.Approximately 6-7 months post infection D. immitis adults reach maturityand sexually reproduce in the pulmonary artery leading to microfilaria(MF) production and circulation in the blood of the dog, thus completingthe heartworm life cycle.

The most commonly used heartworm preventatives are the macrocycliclactones (MLs) such as ivermectin, moxidectin and selamectin. Theseagents are administered on a monthly basis whereby they kill D. immitisL3 and L4 worms acquired by the host within the previous 30 days. Theirprimary action is to disrupt the heartworm life cycle by killing L3 andL4 worms thus preventing adult formation and subsequent disease. Whilevery effective at preventing heartworm disease, owners are advised totest dogs for existing heartworm infections (i.e. heartworm positivedogs) prior to starting treatment with MLs due to their potential tokill circulating microfilariae. A rapid decrease in the numbers ofmicrofilariae in the blood can lead to hypersensitivity-type reactionsand circulatory shock (e.g. anaphylaxis), presumably due to dead ordying microfilariae. These potential adverse effects can belife-threatening to the dog and as such are presented as cautionstatements on many ML product labels. Therefore, the discovery of anovel heartworm preventative that would selectively target L3 and L4stage worms versus microfilariae would offer a potential safetyadvantage. By not killing circulating microfilariae in heartwormpositive dogs, a targeted treatment would prevent the adverse effectsknown to occur with other heartworm preventatives that lack D. immitisstage selectivity.

Thus, alternative, and more effective, treatments for filarial wormdiseases are needed.

Citation or identification of any reference in this application is notto be construed as an admission that the reference is prior art to thepresent application.

SUMMARY

Provided herein are Heterocyclic Compounds of formula (I):

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof, wherein W, X, Y, R¹, R², and R^(N) are as definedherein.

Also provided herein are Heterocyclic Compounds of formula (II):

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof, wherein W, X, Y, R¹, R², and R^(N) are as definedherein.

In one aspect, provided herein are Heterocyclic Compounds as describedin the instant disclosure, such as, for example, a Heterocyclic Compoundof formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II),or formula (IIa), or a compound from Table 1.

In one aspect, provided herein are pharmaceutical compositionscomprising an effective amount of a Heterocyclic Compound, as describedherein, and a pharmaceutically acceptable carrier, excipient or vehicle.In some embodiments the pharmaceutical composition is suitable for oral,parenteral, mucosal, transdermal or topical administration.

In one aspect, provided herein are methods of treating a subjectinfected with a helminth. In another aspect, provided herein are uses ofHeterocyclic Compounds for treating or preventing helminthic infections,comprising administering to a subject affected by helminthic infectionsan effective amount of a Heterocyclic Compound as described herein. Inone aspect the helminthic infection is a filarial infection.

In one aspect, provided herein are methods of treating a subjectinfected with a filarial worm. In another aspect, provided herein areuses of Heterocyclic Compounds for treating or preventing filarialinfections, comprising administering to a subject affected by filarialinfections an effective amount of a Heterocyclic Compound as describedherein.

In certain embodiments, the methods described herein includesadministering a therapeutically effective amount of a compound offormula (I), formula (Ia), formula (Ib), formula (Ic), formula (II),formula (IIa), or a compound from Table 1, or a pharmaceuticallyacceptable salt, tautomer, isotopologue, or stereoisomer thereof, to thesubject.

The compounds of the present invention are useful for the treatment ofhelminthic diseases where the helminths are categorized as cestodes(tapeworms), nematodes (roundworms) and trematodes (flatworms orflukes). Non-limiting examples of filarial nematodes within theOnchocercidae Family include the genus Brugia spp. (i.e., B. malayi, B.pahangi, B. timori, and the like), Wuchereria spp. (i.e., W. bancrofti,and the like), Dirofilaria spp. (D. immitis, D. repens, D. ursi, D.tenuis, D. spectans, D. lutrae, and the like), Dipetalonema spp. (i.e.,D. reconditum, D. repens, and the like), Onchocerca spp. (i.e., O.gibsoni, O. gutturosa, O. volvulus, and the like), Elaeophora spp. (E.bohmi, E. elaphi, E. poeli, E. sagitta, E. schneideri, and the like),Mansonella spp. (i.e., M. ozzardi, M. perstans, and the like), and Loaspp. (i.e., L. loa). In certain embodiments, the filarial worm isOnchocerca volvulus. In certain embodiments, the filarial worm isWuchereria bancrofti. In certain embodiments, the filarial worm isBrugia malayi. In certain embodiments, the filarial worm is Brugiatimori. In certain embodiments, the filarial worm is Mansonella. Incertain embodiments, the filarial worm is Dirofilaria immitis. In someembodiments, the nematode is Haemonchus contortus.

In one aspect, provided herein are uses of Heterocyclic Compounds fortreating or preventing helminthic infections, comprising administeringto a subject affected by helminthic infection an effective amount of aHeterocyclic Compound as described herein. In another aspect, providedherein are uses of Heterocyclic Compounds for treating or preventingfilarial worm infections, wherein the methods comprise administering toa subject affected by filarial worm infections an effective amount of aHeterocyclic Compound as described herein.

In one aspect, provided herein is a Heterocyclic Compound for use as amedicament. In a particular embodiment, provided herein is theHeterocyclic Compound for use in a method for the treatment orprevention of a helminthic infection, the method comprisingadministering to a subject an effective amount of the HeterocyclicCompound. In a particular embodiment, provided herein is theHeterocyclic Compound for use in a method for the treatment orprevention of a filarial worm infection, the method comprisingadministering to a subject an effective amount of the HeterocyclicCompound.

In another aspect provided herein are methods for preparing HeterocyclicCompounds as described herein.

The present embodiments can be understood more fully by reference to thedetailed description and examples, which are intended to exemplifynon-limiting embodiments.

DETAILED DESCRIPTION Definitions

As used herein, the terms “comprising” and “including” can be usedinterchangeably. The terms “comprising” and “including” are to beinterpreted as specifying the presence of the stated features orcomponents as referred to, but does not preclude the presence oraddition of one or more features, or components, or groups thereof.Additionally, the terms “comprising” and “including” are intended toinclude examples encompassed by the term “consisting of”. Consequently,the term “consisting of” can be used in place of the terms “comprising”and “including” to provide for more specific embodiments of theinvention.

The term “consisting of” means that a subject-matter has at least 90%,95%, 97%, 98% or 99% of the stated features or components of which itconsists. In another embodiment the term “consisting of” excludes fromthe scope of any succeeding recitation any other features or components,excepting those that are not essential to the technical effect to beachieved.

As used herein, the term “or” is to be interpreted as an inclusive “or”meaning any one or any combination. Therefore, “A, B or C” means any ofthe following: “A; B; C; A and B; A and C; B and C; A, B and C”. Anexception to this definition will occur only when a combination ofelements, functions, steps or acts are in some way inherently mutuallyexclusive.

As used herein and unless otherwise specified, an “alkyl” group is asaturated, partially saturated, or unsaturated straight chain orbranched non-cyclic hydrocarbon having from 1 to 10 carbon atoms,typically from 1 to 8 carbons or, in some embodiments, from 1 to 6, 1 to4, or 2 to 6 or carbon atoms. Representative alkyl groups include-methyl, -ethyl, -n-propyl, -n-butyl, -n-pentyl and -n-hexyl; whilesaturated branched alkyls include -isopropyl, -sec-butyl, -isobutyl,-tert-butyl, -isopentyl, -neopentyl, tert-pentyl, -2-methylpentyl,-3-methylpentyl, -4-methylpentyl, -2,3-dimethylbutyl and the like. An“alkenyl” group is an alkyl group that contains one or morecarbon-carbon double bonds. An “alkynyl” group is an alkyl group thatcontains one or more carbon-carbon triple bonds. Examples of unsaturatedalkyl groups include, but are not limited to, vinyl, allyl, —CH═CH(CH₃),—CH═C(CH₃)₂, —C(CH₃)═CH₂, —C(CH₃)═CH(CH₃), —C(CH₂CH₃)═CH₂, —C≡CH,—C≡C(CH₃), —C≡C(CH₂CH₃), —CH₂C≡CH, —CH₂C≡C(CH₃) and —CH₂C≡C(CH₂CH₃),among others. An alkyl group can be substituted or unsubstituted. Whenthe alkyl groups described herein are said to be “substituted,” they maybe substituted with any substituent or substituents as those found inthe exemplary compounds and embodiments disclosed herein, as well ashalogen; hydroxy; alkoxy; cycloalkyloxy, aryloxy, heterocyclyloxy,heteroaryloxy, heterocycloalkyoxy, cycloalkylalkyloxy, aralkyloxy,heterocyclylalkyloxy, heteroarylalkyloxy, heterocycloalkyalkyloxy; oxo(═O); amino, alkylamino, cycloalkylamino, arylamino, heterocyclylamino,heteroarylamino, heterocycloalkylamino; imino; imido; amidino;guanidino; enamino; acylamino; sulfonylamino; urea, nitrourea; oxime;hydroxylamino; alkoxyamino; aralkoxyamino; hydrazino; hydrazido;hydrazono; azido; nitro; thio (—SH), alkylthio; ═S; sulfinyl; sulfonyl;aminosulfonyl; phosphonate; phosphinyl; acyl; formyl; carboxy; ester;carbamate; amido; cyano; isocyanato; isothiocyanato; cyanato;thiocyanato; or —B(OH)₂.

As used herein and unless otherwise specified, a “cycloalkyl” group is asaturated, or partially saturated cyclic alkyl group of from 3 to 10carbon atoms having a single cyclic ring or multiple condensed orbridged rings which can be optionally substituted. In some embodiments,the cycloalkyl group has 3 to 8 ring members, whereas in otherembodiments the number of ring carbon atoms ranges from 3 to 5, 3 to 6,or 3 to 7. Such cycloalkyl groups include, by way of example, singlering structures such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl,2-methylcyclopentyl, 2-methylcyclooctyl, and the like, or multiple orbridged ring structures such as 1-bicyclo[1.1.1]pentyl,bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl,adamantyl and the like. Examples of unsaturared cycloalkyl groupsinclude cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl,pentadienyl, hexadienyl, among others. A cycloalkyl group can besubstituted or unsubstituted. Such substituted cycloalkyl groupsinclude, by way of example, cyclohexanol and the like.

As used herein and unless otherwise specified, an “aryl” group is anaromatic carbocyclic group of from 6 to 14 carbon atoms having a singlering (e.g., phenyl) or multiple condensed rings (e.g., naphthyl oranthryl). In some embodiments, aryl groups contain 6-14 carbons, and inothers from 6 to 12 or even 6 to 10 carbon atoms in the ring portions ofthe groups. Particular aryl groups include phenyl, biphenyl, naphthyland the like. An aryl group can be substituted or unsubstituted. Thephrase “aryl groups” also includes groups containing fused rings, suchas fused aromatic-aliphatic ring systems (e.g., indanyl,tetrahydronaphthyl, and the like).

As used herein and unless otherwise specified, a “heteroaryl” group isan aromatic ring system having one to four heteroatoms as ring atoms ina heteroaromatic ring system, wherein the remainder of the atoms arecarbon atoms. In some embodiments, heteroaryl groups contain 3 to 6 ringatoms, and in others from 6 to 9 or even 6 to 10 atoms in the ringportions of the groups. Suitable heteroatoms include oxygen, sulfur andnitrogen. In certain embodiments, the heteroaryl ring system ismonocyclic or bicyclic. Non-limiting examples include but are notlimited to, groups such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl,tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g.,benzo[d]isoxazolyl), thiazolyl, pyrolyl, pyridazinyl, pyrimidyl,pyrazinyl, thiophenyl, benzothiophenyl, furanyl, benzofuranyl, indolyl(e.g., indol-2-onyl), isoindolin-1-onyl, azaindolyl, pyrrolopyridyl(e.g., 1H-pyrrolo[2,3-b]pyridyl), indazolyl, benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), azabenzimidazolyl, imidazopyridyl (e.g.,1H-imidazo[4,5-b]pyridyl), pyrazolopyridyl, triazolopyridyl,benzotriazolyl (e.g., 1H-benzo[d][1,2,3]triazolyl), benzoxazolyl (e.g.,benzo[d]oxazolyl), benzothiazolyl, benzothiadiazolyl, isoxazolopyridyl,thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,isoquinolinyl, 3,4-dihydroisoquinolin-1(2H)-onyl, tetrahydroquinolinyl,quinoxalinyl, and quinazolinyl groups. A heteroaryl group can besubstituted or unsubstituted.

As used herein and unless otherwise specified, a “heterocyclyl” is anaromatic ring system (also referred to as heteroaryl) or non-aromaticcycloalkyl (also referred to as heterocycloalkyl) in which one to fourof the ring carbon atoms are independently replaced with a heteroatom.Suitable heteroatoms include oxygen, sulfur and nitrogen. In someembodiments, heterocyclyl groups include 3 to 10 ring members, whereasother such groups have 3 to 5, 3 to 6, or 3 to 8 ring members.Heterocyclyls can also be bonded to other groups at any ring atom (i.e.,at any carbon atom or heteroatom of the heterocyclic ring). Aheterocyclyl group can be substituted or unsubstituted. Heterocyclylgroups encompass unsaturated, partially saturated and saturated ringsystems, such as, for example, imidazolyl, imidazolinyl andimidazolidinyl (e.g., imidazolidin-4-onyl or imidazolidin-2,4-dionyl)groups. The phrase heterocyclyl includes fused ring species, includingthose comprising fused aromatic and non-aromatic groups, such as, forexample, 1- and 2-aminotetraline, benzotriazolyl (e.g.,1H-benzo[d][1,2,3]triazolyl), benzimidazolyl (e.g.,1H-benzo[d]imidazolyl), 2,3-dihydrobenzo[1,4]dioxinyl, andbenzo[1,3]dioxolyl. The phrase also includes bridged polycyclic ringsystems containing a heteroatom such as, but not limited to,quinuclidyl. Representative examples of a heterocyclyl group include,but are not limited to, aziridinyl, azetidinyl, azepanyl, oxetanyl,pyrrolidyl, imidazolidinyl (e.g., imidazolidin-4-onyl orimidazolidin-2,4-dionyl), pyrazolidinyl, thiazolidinyl,tetrahydrothiophenyl, tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl,pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, benzisoxazolyl (e.g.,benzo[d]isoxazolyl), thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl,oxadiazolyl, piperidyl, piperazinyl (e.g., piperazin-2-onyl),morpholinyl, thiomorpholinyl, tetrahydropyranyl (e.g.,tetrahydro-2H-pyranyl), tetrahydrothiopyranyl, oxathianyl, dioxyl,dithianyl, pyranyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl,triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl,1,4-dioxaspiro[4.5]decanyl, homopiperazinyl, quinuclidyl, indolyl (e.g.,indol-2-onyl), isoindolin-1-onyl, indolinyl, isoindolyl, isoindolinyl,azaindolyl, pyrrolopyridyl (e.g, 1H-pyrrolo[2,3-b]pyridyl), indazolyl,indolizinyl, benzotriazolyl (e.g. 1H-benzo[d][1,2,3]triazolyl),benzimidazolyl (e.g., 1H-benzo[d]imidazolyl or1H-benzo[d]imidazol-2(3H)-onyl), benzofuranyl, benzothiophenyl,benzothiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl,benzoxathiinyl, benzothiazinyl, benzoxazolyl (e.g., benzo[d]oxazolyl),benzothiazolyl, benzothiadiazolyl, benzo[1,3]dioxolyl, pyrazolopyridyl(e.g., 1H-pyrazolo[3,4-b]pyridyl, 1H-pyrazolo[4,3-b]pyridyl),azabenzimidazolyl, imidazopyridyl (e.g., 1H-imidazo[4,5-b]pyridyl),triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl,guaninyl, quinolinyl, isoquinolinyl, 3,4-dihydroisoquinolin-1(2H)-onyl,quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl,naphthyridinyl, pteridinyl, thianaphthalenyl, dihydrobenzothiazinyl,dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl,tetrahydroindolyl, tetrahydroindazolyl, tetrahydrobenzimidazolyl,tetrahydrobenzotriazolyl, tetrahydropyrrolopyridyl,tetrahydropyrazolopyridyl, tetrahydroimidazopyridyl,tetrahydrotriazolopyridyl, tetrahydropyrimidin-2(1H)-one andtetrahydroquinolinyl groups. Representative non-aromatic heterocyclylgroups do not include fused ring species that comprise a fused aromaticgroup. Examples of non-aromatic heterocyclyl groups include aziridinyl,azetidinyl, azepanyl, pyrrolidyl, imidazolidinyl (e.g.,imidazolidin-4-onyl or imidazolidin-2,4-dionyl), pyrazolidinyl,thiazolidinyl, tetrahydrothiophenyl, tetrahydrofuranyl, piperidyl,piperazinyl (e.g., piperazin-2-onyl), morpholinyl, thiomorpholinyl,tetrahydropyranyl (e.g., tetrahydro-2H-pyranyl), tetrahydrothiopyranyl,oxathianyl, dithianyl, 1,4-dioxaspiro[4.5]decanyl, homopiperazinyl,quinuclidyl, or tetrahydropyrimidin-2(1H)-one. Representativesubstituted heterocyclyl groups may be mono-substituted or substitutedmore than once, such as, but not limited to, pyridyl or morpholinylgroups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstitutedwith various substituents such as those listed below.

As used herein and unless otherwise specified, a “cycloalkylalkyl” groupis a radical of the formula: -alkyl-cycloalkyl, wherein alkyl andcycloalkyl are defined above. Substituted cycloalkylalkyl groups may besubstituted at the alkyl, the cycloalkyl, or both the alkyl and thecycloalkyl portions of the group. Representative cycloalkylalkyl groupsinclude but are not limited to cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclobutylethyl,cyclopentylethyl, cyclohexylethyl, cyclopentylpropyl, cyclohexylpropyland the like.

As used herein and unless otherwise specified, an “aralkyl” group is aradical of the formula: -alkyl-aryl, wherein alkyl and aryl are definedabove. Substituted aralkyl groups may be substituted at the alkyl, thearyl, or both the alkyl and the aryl portions of the group.Representative aralkyl groups include but are not limited to benzyl andphenethyl groups and aralkyl groups wherein the aryl group is fused to acycloalkyl group such as indan-4-yl ethyl.

As used herein and unless otherwise specified, a “heterocyclylalkyl”group is a radical of the formula: -alkyl-heterocyclyl, wherein alkyland heterocyclyl are defined above. A “heteroarylalkyl” group is aradical of the formula: -alkyl-heteroaryl, wherein alkyl and heteroarylare defined above. A “heterocycloalkylalkyl” group is a radical of theformula: -alkyl-heterocycloalkyl, wherein alkyl and heterocycloalkyl aredefined above. Substituted heterocyclylalkyl groups may be substitutedat the alkyl, the heterocyclyl, or both the alkyl and the heterocyclylportions of the group. Representative heterocylylalkyl groups includebut are not limited to morpholin-4-yl ethyl, morpholin-4-yl propyl,furan-2-yl methyl, furan-3-yl methyl, pyridin-3-yl methyl,tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

As used herein and unless otherwise specified, a “halogen” is fluorine,chlorine, bromine or iodine.

As used herein and unless otherwise specified, a “hydroxyalkyl” group isan alkyl group as described above substituted with one or more hydroxygroups.

As used herein and unless otherwise specified, an “alkoxy” group is—O-(alkyl), wherein alkyl is defined above. An “alkylthio” group is—S-(alkyl), wherein alkyl is defined above.

As used herein and unless otherwise specified, an “alkoxyalkyl” group is-(alkyl)-O-(alkyl), wherein alkyl is defined above.

As used herein and unless otherwise specified, a “cycloalkyloxy” groupis —O-(cycloalkyl), wherein cycloalkyl is defined above.

As used herein and unless otherwise specified, an “aryloxy” group is—O-(aryl), wherein aryl is defined above.

As used herein and unless otherwise specified, a “heterocyclyloxy” groupis —O-(heterocyclyl), wherein heterocyclyl is defined above. A“heteroaryloxy” group is —O-(heteroaryl), wherein heteroaryl is definedabove. A “heterocycloalkyloxy” group is —O-(heterocycloalkyl), whereinheterocycloalkyl is defined above.

As used herein and unless otherwise specified, an “amino” group is aradical of the formula: —NH₂, —NH(R^(#)), or —N(R^(#))₂, wherein eachR^(#) is independently an alkyl, cycloalkyl, cycloalkylalkyl, aryl,aralkyl, heterocyclyl (e.g., heteroaryl or heterocycloalkyl), orheterocyclylalkyl (e.g., heteroarylalkyl or heterocycloalkylalkyl) groupdefined above, each of which is independently substituted orunsubstituted.

In one embodiment, an “amino” group is an “alkylamino” group, which is aradical of the formula: —NH-alkyl or —N(alkyl)₂, wherein each alkyl isindependently defined above. The term “cycloalkylamino”, “arylamino”,“heterocyclylamino”, “heteroarylamino”, “heterocycloalkylamino”, or thelike, mirrors the above description for “alkylamino” where the term“alkyl” is replaced with “cycloalkyl”, “aryl”, “heterocyclyl”,“heteroaryl”, “heterocycloalkyl”, or the like, respectively.

As used herein and unless otherwise specified, a “carboxy” group is aradical of the formula: —C(O)OH.

As used herein and unless otherwise specified, an “acyl” group is aradical of the formula: —C(O)(R^(#)) or —C(O)H, wherein R^(#) is definedabove. A “formyl” group is a radical of the formula: —C(O)H.

As used herein and unless otherwise specified, an “amido” group is aradical of the formula: —C(O)—NH₂, —C(O)—NH(R^(#)), —C(O)—N(R^(#))₂,—NH—C(O)H, —NH—C(O)—(R^(#)), —N(R^(#))—C(O)H, or —N(R^(#))—C(O)—(R^(#)),wherein each R^(#) is independently defined above.

In one embodiment, an “amido” group is an “aminocarbonyl” group, whichis a radical of the formula: —C(O)—NH₂, —C(O)—NH(R^(#)),—C(O)—N(R^(#))₂, wherein each R^(#) is independently defined above.

In one embodiment, an “amido” group is an “acylamino” group, which is aradical of the formula: —NH—C(O)H, —NH—C(O)—(R^(#)), —N(R^(#))—C(O)H, or—N(R^(#))—C(O)—(R^(#)), wherein each R^(#) is independently definedabove.

As used herein and unless otherwise specified, a “sulfonylamino” groupis a radical of the formula: —NHSO₂(R^(#)) or —N(R^(#))SO₂(R^(#)),wherein each R^(#) is defined above.

As used herein and unless otherwise specified, an “ester” group is aradical of the formula: —C(O)—O—(R^(#)) or —O—C(O)—(R^(#)), whereinR^(#) is defined above.

In one embodiment, an “ester” group is an “alkoxycarbonyl” group, whichis a radical of the formula: —C(O)—O-(alkyl), wherein alkyl is definedabove. The term “cycloalkyloxycarbonyl”, “aryloxycarbonyl”,“heterocyclyloxycarbonyl”, “heteroaryloxycarbonyl”,“heterocycloalkyloxycarbonyl”, or the like, mirrors the abovedescription for “alkoxycarbonyl” where the term “alkoxy” is replacedwith “cycloalkyloxy”, “aryloxy”, “heterocyclyloxy”, “heteroaryloxy”,“heterocycloalkyloxy”, or the like, respectively.

As used herein and unless otherwise specified, a “carbamate” group is aradical of the formula: —O—C(O)—NH₂, —O—C(O)—NH(R^(#)),—O—C(O)—N(R^(#))₂, —NH—C(O)—O—(R^(#)), or —N(R^(#))—C(O)—O—(R^(#)),wherein each R^(#) is independently defined above.

As used herein and unless otherwise specified, a “urea” group is aradical of the formula: —NH(CO)NH₂, —NHC(O)NH(R^(#)), —NHC(O)N(R^(#))₂,—N(R^(#))C(O)NH₂, —N(R^(#))C(O)NH(R^(#)), or —N(R^(#))C(O)N(R^(#))₂,wherein each R^(#) is independently defined above.

As used herein and unless otherwise specified, a “sulfinyl” group is aradical of the formula: —S(O)R^(#), wherein R^(#) is defined above.

As used herein and unless otherwise specified, a “sulfonyl” group is aradical of the formula: —S(O)₂R^(#), wherein R^(#) is defined above.

As used herein and unless otherwise specified, an “aminosulfonyl” groupis a radical of the formula: —SO₂NH₂, —SO₂NH(R^(#)), or —SO₂N(R^(#))₂,wherein each R^(#) is independently defined above.

When the groups described herein, with the exception of alkyl group, aresaid to be “substituted,” they may be substituted with any appropriatesubstituent or substituents. Illustrative examples of substituents arethose found in the exemplary compounds and embodiments disclosed herein,as well as halogen; alkyl, alkenyl, alkynyl, cycloalkyl, aryl,heterocyclyl, heteroaryl, heterocycloalky, cycloalkylalkyl, aralkyl,heterocyclylalkyl, heteroarylalkyl, heterocycloalkyalkyl, optionallyfurther substituted; hydroxy; alkoxy; cycloalkyloxy, aryloxy,heterocyclyloxy, heteroaryloxy, heterocycloalkyoxy, cycloalkylalkyloxy,aralkyloxy, heterocyclylalkyloxy, heteroarylalkyloxy,heterocycloalkyalkyloxy; oxo (═O); oxide (e.g., a nitrogen atomsubstituted with an oxide is called N-oxide); amino, alkylamino,cycloalkylamino, arylamino, heterocyclylamino, heteroarylamino,heterocycloalkylamino; imino; imido; amidino; guanidino; enamino;acylamino; sulfonylamino; urea, nitrourea; oxime; hydroxylamino;alkoxyamino; aralkoxyamino; hydrazino; hydrazido; hydrazono; azido;nitro; thio (—SH), alkylthio; ═S; sulfinyl; sulfonyl; aminosulfonyl;phosphonate; phosphinyl; acyl; formyl; carboxy; ester; carbamate; amido;cyano; isocyanato; isothiocyanato; cyanato; thiocyanato; or —B(OH)₂.

As used herein, the term “Heterocyclic Compound” includes compounds offormula (I), formula (Ia), formula (Ib), formula (Ic), formula (II),formula (IIa), and Table 1 as well as to further embodiments ofcompounds of formula (I), formula (Ia), formula (Ib), formula (Ic),formula (II), formula (IIa), and Table 1 provided herein. For example,the term “Heterocyclic Compound” includes deuterated compounds offormula (I), formula (Ia), formula (Ib), formula (Ic), formula (II),formula (IIa), and Table 1. In one embodiment, a “Heterocyclic Compound”is a compound set forth in Table 1. In certain embodiments, the term“Heterocyclic Compound” includes pharmaceutically acceptable salts,tautomers, isotopologues, and/or stereoisomers of the HeterocyclicCompounds provided herein.

As used herein, the term “pharmaceutically acceptable salt(s)” refers toa salt prepared from a pharmaceutically acceptable non-toxic acid orbase including an inorganic acid and base and an organic acid and base.Suitable pharmaceutically acceptable base addition salts of thecompounds of formula (I), formula (Ia), formula (Ib), formula (Ic), andTable 1, include, but are not limited to, metallic salts made fromaluminum, calcium, lithium, magnesium, potassium, sodium and zinc ororganic salts made from lysine, N,N′-dibenzylethylenediamine,chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine(N-methyl-glucamine) and procaine. Suitable non-toxic acids include, butare not limited to, inorganic and organic acids such as acetic, alginic,anthranilic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethenesulfonic, formic, fumaric, furoic, galacturonic, gluconic,glucuronic, glutamic, glycolic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phenylacetic, phosphoric, propionic, salicylic, stearic,succinic, sulfanilic, sulfuric, tartaric acid, and p-toluenesulfonicacid. Specific non-toxic acids include hydrochloric, hydrobromic,maleic, phosphoric, sulfuric, and methanesulfonic acids. Examples ofspecific salts thus include hydrochloride and mesylate salts. Others arewell-known in the art, see for example, Remington's PharmaceuticalSciences, 18^(th) eds., Mack Publishing, Easton Pa. (1990) or Remington:The Science and Practice of Pharmacy, 19^(th) eds., Mack Publishing,Easton Pa. (1995).

As used herein and unless otherwise indicated, the term “stereoisomer”or “stereomerically pure” means one stereoisomer of a HeterocyclicCompound that is substantially free of other stereoisomers of thatcompound. For example, a stereomerically pure compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure compound having two chiral centers willbe substantially free of other diastereomers of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, greater than about 90% by weight ofone stereoisomer of the compound and less than about 10% by weight ofthe other stereoisomers of the compound, greater than about 95% byweight of one stereoisomer of the compound and less than about 5% byweight of the other stereoisomers of the compound, or greater than about97% by weight of one stereoisomer of the compound and less than about 3%by weight of the other stereoisomers of the compound. The HeterocyclicCompounds can have chiral centers and can occur as racemates, individualenantiomers or diastereomers, and mixtures thereof. All such isomericforms are included within the embodiments disclosed herein, includingmixtures thereof.

The use of stereomerically pure forms of such Heterocyclic Compounds, aswell as the use of mixtures of those forms, are encompassed by theembodiments disclosed herein. For example, mixtures comprising equal orunequal amounts of the enantiomers of a particular Heterocyclic Compoundmay be used in methods and compositions disclosed herein. These isomersmay be asymmetrically synthesized or resolved using standard techniquessuch as chiral columns or chiral resolving agents. See, e.g., Jacques,J., et al., Enantiomers, Racemates and Resolutions (Wiley-Interscience,New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977);Eliel, E. L., Stereochemistry of Carbon Compounds (McGraw-Hill, N Y,1962); and Wilen, S. H., Tables of Resolving Agents and OpticalResolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, NotreDame, Ind., 1972).

It should also be noted the Heterocyclic Compounds can include E and Zisomers, or a mixture thereof, and cis and trans isomers or a mixturethereof. In certain embodiments, the Heterocyclic Compounds are isolatedas either the E or Z isomer. In other embodiments, the HeterocyclicCompounds are a mixture of the E and Z isomers.

“Tautomers” refers to isomeric forms of a compound that are inequilibrium with each other. The concentrations of the isomeric formswill depend on the environment the compound is found in and may bedifferent depending upon, for example, whether the compound is a solidor is in an organic or aqueous solution. For example, in aqueoussolution, pyrazoles may exhibit the following isomeric forms, which arereferred to as tautomers of each other:

As readily understood by one skilled in the art, a wide variety offunctional groups and other structures may exhibit tautomerism and alltautomers of compounds of formula (I), formula (Ia), formula (Ib),formula (Ic), formula (II), formula (IIa), and Table 1 are within thescope of the present invention.

It should also be noted the Heterocyclic Compounds can contain unnaturalproportions of atomic isotopes at least one of the atoms. For example,the compounds may be radiolabeled with radioactive isotopes, such as forexample tritium (³H), iodine-125 (¹²⁵I), sulfur-35 (³⁵S), or carbon-14(¹⁴C), or may be isotopically enriched, such as with carbon-13 (¹³C), ornitrogen-15 (¹⁵N). As used herein, an “isotopologue” is an isotopicallyenriched compound. The term “isotopically enriched” refers to an atomhaving an isotopic composition other than the natural isotopiccomposition of that atom. “Isotopically enriched” may also refer to acompound containing at least one atom having an isotopic compositionother than the natural isotopic composition of that atom. The term“isotopic composition” refers to the amount of each isotope present fora given atom. Radiolabeled and isotopically enriched compounds areuseful as therapeutic agents, e.g., cancer and inflammation therapeuticagents, research reagents, e.g., binding assay reagents, and diagnosticagents, e.g., in vivo imaging agents. All isotopic variations of theHeterocyclic Compounds as described herein, whether radioactive or not,are intended to be encompassed within the scope of the embodimentsprovided herein. In some embodiments, there are provided isotopologuesof the Heterocyclic Compounds, for example, the isotopologues arecarbon-13, or nitrogen-15 enriched Heterocyclic Compounds. As usedherein, “deuterated”, means a compound wherein at least one hydrogen (H)has been replaced by deuterium (indicated by D or ²H), that is, thecompound is enriched in deuterium in at least one position.

It should be noted that if there is a discrepancy between a depictedstructure and a name for that structure, the depicted structure is to beaccorded more weight.

As used herein, “inhibit” and “inhibition” mean that a specifiedresponse of a designated activity (e.g., worm motility) is comparativelydecreased in the presence of a Heterocyclic Compound. Inhibition of wormmotility, for example motility of Onchocerca volvulus, Brugia malayiand/or Brugia timori, can be determined by the assays described herein.

“Treating” as used herein, means an alleviation, in whole or in part, ofa disorder, disease or condition, or one or more of the symptomsassociated with a disorder, disease, or condition, or slowing or haltingof further progression or worsening of those symptoms, or alleviating oreradicating the cause(s) of the disorder, disease, or condition itself.In one embodiment, the disorder, disorder or condition is a helminthicinfection.

“Preventing” as used herein, means a method of delaying and/orprecluding the onset, recurrence or spread, in whole or in part, of adisorder, disease or condition; barring a subject from acquiring adisorder, disease, or condition; or reducing a subject's risk ofacquiring a disorder, disease, or condition. In one embodiment, thedisorder, disorder or condition is a helminthic infection.

The term “effective amount” in connection with a Heterocyclic Compoundmeans an amount capable of treating or preventing a disorder, disease orcondition, or symptoms thereof, disclosed herein. In one embodiment, thedisorder, disorder or condition is a helminthic infection.

The term “subject” or “patient” includes humans and other primates aswell as domesticated and semi-domesticated animals including, but notlimited to, poultry, honeybees, cows, sheep, cattle, goats, pigs,horses, dogs, cats, rabbits, rats, mice and the like. The term “poultry”encompasses all types of domestic fowl, including, but not limited tochickens, turkey, ducks, geese, the ratite group of birds and gamebirds. In certain embodiments, the subject is a human. In certainembodiments, the subject is a dog. In certain embodiments, the subjectis a cat. In certain embodiments, the subject is a livestock. In certainembodiments, the subject is a cow. In certain embodiments, the subjectis a sheep. In another embodiment, the subject is a goat.

The term “combination” or administration “in combination” includesadministration as a mixture, simultaneous administration using separateformulations, and consecutive administration in any order.

The term “helminthic infections” or “helminth infection” as used hereinrefers to infections that are caused by parasitic worms. An infectioncaused by a helminth, known as “helminthiasis” (plural “helminthiases”),is any macroparasitic disease of humans and other animals in which apart of the body is infected with parasitic worms, known as helminths.There are numerous species of these parasites, which are broadlyclassified into tapeworms, flukes, and roundworms.

The term “filariasis” as used herein refers to helminth infections thatare caused by filarial nematodes. Non-limiting examples of filarialnematodes within the Onchocercidae family include the genus Brugia spp.(i.e., B. malayi, B. pahangi, B. timori, and the like), Wuchereria spp.(i.e., W. bancrofti, and the like), Dirofilaria spp. (D. immitis, D.repens, D. ursi, D. tenuis, D. spectans, D. lutrae, and the like),Dipetalonema spp. (i.e., D. reconditum, D. repens, and the like),Onchocerca spp. (i.e., O. gibsoni, O. gutturosa, O. volvulus, and thelike), Elaeophora spp. (E. bohmi, E. elaphi, E. poeli, E. sagitta, E.schneideri, and the like), Mansonella spp. (i.e., M. ozzardi, M.perstans, and the like), and Loa spp. (i.e., L. loa). An infection isthe colonization of a host organism by parasite species. Infections withhuman filarial nematodes can cause lymphatic filariasis oronchocerciasis. The term “lymphatic filariasis” refers to an infectionwith the nematodes Wuchereria bancrofti, Brugia malayi or Brugia timori.The term “onchocerciasis” refers to an infection with the nematodeOnchocerca volvulus. Lymphatic filariasis may cause hydrocoele,lymphoedema, and elephantiasis. Onchocerciasis may cause skininflammation and blindness, so called River Blindness. In dogs, aninfection with nematode species called Dirofilaria immitis orDirofilaria repens causes dirofilariasis. In sheep and goats andinfection with a nematoide species called Haemonchus contortus causeshaemonchosis.

The term “worm” or “nematode” as used interchangeably herein refers toall life stages of the organism, such as an egg, an unfertilized egg, afertilized egg, a larva or juvenile worm, a larva in any one of fourlarval stages (L1, L2, L3, L4), a worm in sexually immature stage (stageL5), a worm in mature stage, a worm in fully mature stage, an adultworm, a worm in pre-parasitic stage, or a worm in parasitic stage.

The term “microfilaria” or “mf” as used herein refers to an early stagein the life cycle of certain parasitic nematodes. Microfilaria isconsidered to be the first larva stage also referred to as L1. The terms“microfilaria,” “mf,” or “L1” are used alternatively and/orinterchangeably.

The term “macrofilaria” as used herein refers to the adult stage in thelife cycle of certain parasitic nematodes.

Unless otherwise defined, the technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this application belongs.

Surprisingly, it was found that the compounds disclosed herein areeffective in the treatment of helminthic infections, for example,filarial infections. In vitro and in vivo results demonstrated that thecompounds disclosed herein are effective against filarial nematodes. Insome embodiments, the compounds disclosed herein surprisingly presenteddistinct activity between parasitic nematodes in adult and juvenilestage. In some such embodiments, the compounds disclosed herein areselectively effective against adult filarial nematodes (also referred toas macrofilaricidal activity). In other embodiments, the compoundsdisclosed herein are selectively effective against the juvenile stagefilarial nematodes (also referred to as microfilaricidal activity).Therefore, the compounds disclosed herein have the potential to bepotent anti-filarial drugs.

Compounds

Provided herein are Heterocyclic Compounds having the following formula(I):

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof, wherein:

W is N or NR;

X is N, NR, O, or S;

Y is N, NR, O, or S;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —SO₂NR₂, —SO₂(substituted orunsubstituted heterocyclyl), —N(R)CO(R⁴), —CON(R⁵)₂, and substituted orunsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl orsubstituted or unsubstituted C₅₋₆ heteroaryl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached form a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached form a substituted or unsubstituted 3 to 6 memberedheterocyclyl;

R^(N) is H, or substituted or unsubstituted C₁₋₅ alkyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In one embodiment, the compound is a compound of formula (Ia)

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof. In some such embodiments, the compound is acompound of formula (Ia), wherein X is NR, O, or S, and Y is N. In othersuch embodiments, the compound is a compound of formula (Ia), wherein Xis O or S, and Y is N.

In other embodiments, the compound is a compound of formula (Ib)

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof. In some such embodiments, the compound is acompound of formula (Ib), wherein X is N, and Y is NR, O, or S. In othersuch embodiments, the compound is a compound of formula (Ib), wherein Xis N, and Y is O or S.

In still other embodiments, the compound is a compound of formula (Ic)

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof. In some such embodiments, the compound is acompound of formula (Ic) wherein X is N and Y is N.

Provided herein are Heterocyclic Compounds having the following formula(II):

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof, wherein:

W is N, NR, or S;

X is N, NR, O, or S;

Y is N, NR, O, or S;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —SO₂NR₂, —SO₂(substituted orunsubstituted heterocyclyl), —N(R)CO(R⁴), —CON(R⁵)₂, and substituted orunsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl orsubstituted or unsubstituted C₅₋₆ heteroaryl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁-3 alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached form a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached form a substituted or unsubstituted 3 to 6 memberedheterocyclyl;

R^(N) is H, or substituted or unsubstituted C₁₋₅ alkyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In other embodiments, the compound is a compound of formula (IIa)

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof. In some such embodiments, the compound is acompound of formula (IIa) wherein Y is N.

In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II)and (IIa), R¹ is substituted with one or more substituents independentlyselected from halogen, CN, substituted or unsubstituted C₁₋₄ alkyl,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted 3-6 membered heterocyclyl, substituted or unsubstitutedC₆₋₁₀ aryl, —NR₂, —COOR, —OR³, —SO₂NR₂, —SO₂(substituted orunsubstituted heterocyclyl), —N(R)CO(R⁴), and —CON(R⁵)₂. In some suchembodiments, R¹ is substituted with one or more substituentsindependently selected from Cl, F, Br, CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —C(CH₃)₃, —CH₂F,—CHF₂, —CF₃; substituted or unsubstituted cycloalkyl selected fromcyclopropyl, cyclobutyl, and cyclopentyl; substituted or unsubstitutedheterocyclyl selected from pyrrolidyl, pyrrolidinonyl, piperidyl,piperazinyl, and morpholinyl; substituted or unsubstituted phenyl; —NH₂,—NHCH₃, —N(CH₃)₂, —COOH, —COOCH₃, —OR³, —SO₂N(CH₃)₂; —SO₂(aziridinyl),—NHCO(R⁴), —N(CH₃)CO(R⁴), —N(CH₂CH₃)CO(R⁴), —N(CH₂CH₂CH₃)CO(R⁴),—N(CH₂CH(CH₃)₂)CO(R⁴), and —CON(R⁵)₂. In some such embodiments, R³ is—CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, cyclohexyl, tetrahydrofuranyl,tetrahydropyranyl, piperidyl, or 1-CH₃-piperidyl. In other suchembodiments, R³ is —CH₃, —CH(CH₃)₂, cyclohexyl, tetrahydropyranyl,piperidyl, or 1-CH₃-piperidyl. In yet other such embodiments, R⁴ isselected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂; substituted orunsubstituted cycloalkyl selected from cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl. For example, R⁴ is selected from —CH₃,—CH₂CH(CH₃)₂, cyclopropyl, cyclobutyl, or cyclopentyl. In otherembodiments, each R⁵ is independently selected from H, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂; substituted or unsubstituted cycloalkyl selectedfrom cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; substituted orunsubstituted -(alkyl)-(cycloalkyl) selected from —CH₂-cyclopropyl,—CH₂-cyclobutyl, and —CH₂-cyclopentyl; or two R⁵ and the nitrogen towhich they are attached form a pyrrolidyl. In some other suchembodiments, each R⁵ is independently selected from H, —CH₃,cyclopropyl, cyclobutyl, cyclobutyl substituted with one or more F, and—CH₂-cyclopropyl; or two R⁵ and the nitrogen to which they are attachedform a pyrrolidyl.

Also provided are compounds of formula (I), (Ia), (Ib), (Ic), (II) and(IIa), wherein R¹ is 2-pyridyl, 3-pyridyl or pyrazinyl. In someembodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II) and(IIa), R¹ is 2-pyridyl, unsubstituted or substituted with one or moresubstituents independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, substituted orunsubstituted aryl, —NR₂, —COOR, —OR³, —SO₂NR₂, —SO₂(substituted orunsubstituted heterocyclyl), —N(R)CO(R⁴), and —CON(R⁵)₂. In someembodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II) and(IIa), R¹ is 2-pyridyl, substituted with one or more substituentsindependently selected from Cl, F, Br, CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F, —CHF₂, —CF₃;substituted or unsubstituted cycloalkyl selected from cyclopropyl,cyclobutyl, and cyclopentyl; substituted or unsubstituted heterocyclylselected from pyrrolidyl, pyrrolidinonyl, piperidyl, piperazinyl, andmorpholinyl; substituted or unsubstituted phenyl; —NH₂, —NHCH₃,—N(CH₃)₂, —COOH, —COOCH₃, —OR³, —SO₂N(CH₃)₂; —SO₂(aziridinyl),—NHCO(R⁴), —N(CH₃)CO(R⁴), —N(CH₂CH₃)CO(R⁴), —N(CH₂CH₂CH₃)CO(R⁴),—N(CH₂CH(CH₃)₂)CO(R⁴), and —CON(R⁵)₂. In still other embodiments ofcompounds of formula (I), (Ia), (Ib), (Ic), (II) and (IIa), R¹ is2-pyridyl, unsubstituted or substituted with one or more substituentsindependently selected from F; CN; —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CHF₂,—CF₃; cyclopropyl, cyclopentyl; pyrrolidyl, pyrrolidinonyl, piperidyl,1-methyl-piperidyl, piperazinyl, piperazinyl substituted with —COCH₃ or—(COCH₂CF₃), morpholinyl; phenyl; —NHCH₃, —N(CH₃)₂; —COOMe; —OCH₃,—OCH(CH₃)₂, —O-(cyclohexyl), —O-piperidyl, —O-tetrahydropyranyl,—O-(1-methyl-piperidyl); —SO₂N(CH₃)₂; —SO₂ (aziridinyl), —NHCOCH₃,—N(CH₃)COCH₃, —N(CH(CH₃)₂)COCH₃, —N(CH₃)CO(CH(CH₃)₂),—N(CH₃)CO(cyclopropyl), —N(CH₃)CO(cyclobutyl), —N(CH₃)CO(cyclopentyl);—CONH₂, —CONHCH₃, —CON(CH₃)₂, —CON(CH₃)cyclopropyl,—CONH(difluorocyclobutyl), —CON(CH₃)(difluorocyclobutyl),—CONH(CH₂-cyclopropyl), and —CO(pyrrolidyl).

In another aspect, also provided are compounds of formula (Ia), whereinX is S and Y is N, and R¹ is 2-pyridyl, unsubstituted or substitutedwith one or more substituents independently selected from F; CN; —CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CHF₂, —CF₃; cyclopropyl, cyclopentyl; pyrrolidyl,pyrrolidinonyl, piperidyl, 1-methyl-piperidyl, piperazinyl, piperazinylsubstituted with COCH₃ or (COCH₂CF₃), morpholinyl; phenyl; —NHCH₃,—N(CH₃)₂; —COOMe; —OCH₃, —OCH(CH₃)₂, —O-piperidyl, —O-tetrahydropyranyl,—O-(1-methyl-piperidyl); —SO₂N(CH₃)₂; —SO₂(aziridinyl), —NHCOCH₃,—N(CH₃)COCH₃, —N(CH(CH₃)₂)COCH₃, —N(CH₃)CO(CH(CH₃)₂),—N(CH₃)CO(cyclopropyl), —N(CH₃)CO(cyclobutyl), —N(CH₃)CO(cyclopentyl);—CONH₂, —CONHCH₃, —CON(CH₃)₂, —CON(CH₃)cyclopropyl,—CONH(difluorocyclobutyl), —CON(CH₃)(difluorocyclobutyl),—CONH(CH₂-cyclopropyl), and —CO(pyrrolidyl).

In another aspect, also provided are compounds of formula (Ib), whereinX is N and Y is S, and R¹ is 2-pyridyl, substituted with one or moresubstituents independently selected from —CH₃, —CH(CH₃)₂, —CF₃, phenyl,—OCH₃, and —O(CH(CH₃)₂).

In still another aspect, provided are compounds of formula (Ia), whereinX is O and Y is N, and R¹ is 2-pyridyl, unsubstituted or substitutedwith one or more substituents independently selected from —CH₃, —CF₃,pyrrolidyl, phenyl, —N(CH₃)₂, —OCH₂CH₃, —O(CH(CH₃)₂),—O-tetrahydropyranyl, —N(CH₃)COCH₃, and —N(CH₃)CO(cyclopropyl).

In another aspect, provided are compounds of formula (Ib), wherein X isN and Y is O, and R¹ is 2-pyridyl, unsubstituted or substituted with oneor more substituents independently selected from —CH₃, —CH(CH₃)₂, —CF₃,phenyl, —N(CH₃)₂, —OCH₃, —O(CH(CH₃)₂), and —O-(cyclohexyl).

In still another aspect, provided are compounds of formula (Ia), whereinX is NH and Y is N, and R¹ is 2-pyridyl, unsubstituted or substitutedwith one or more substituents independently selected from —CH₃, —CF₃,and —N(CH₃)₂.

In yet another aspect, provided are compounds of formula (Ib), wherein Xis N and Y is NH, and R¹ is 2-pyridyl, unsubstituted or substituted withone or more substituents independently selected from —CH₃, phenyl,—O(CH(CH₃)₂), and —O-(cyclohexyl).

Also provided are compounds of formula (Ib), wherein X is N and Y is S,and R¹ is 2-pyridyl, unsubstituted or substituted with —O-(cyclohexyl).

Also provided are compounds of formula (Ib), wherein X is N and Y is N,and R¹ is 3-pyridyl, unsubstituted or substituted with one or moresubstituents independently selected from —CF₃ and —N(CH₃)COCH₃.

Also provided are compounds of formula (Ic), wherein R is —CH₃, X is Nand Y is N, and R¹ is 2-pyridyl, unsubstituted or substituted with oneor more substituents independently selected from —CH₃, —CH(CH₃)₂, —CF₃,—O(CH(CH₃)₂), and —O-(cyclohexyl).

Also provided are compounds of formula (Ic), wherein R is H, X is N andY is N, and R¹ is 2-pyridyl, unsubstituted or substituted with one ormore substituents independently selected from —CF₃ and —N(CH₃)COCH₃.

Also provided are compounds of formula (Ic), wherein R is —CH₃, X is Nand Y is N, and R¹ is 2-pyridyl, unsubstituted or substituted with oneor more substituents independently selected from —OCH(CH₃)₂ and—O-(cyclohexyl).

In another aspect, provided are compounds of formula (IIa), wherein Y isN and R¹ is 2-pyridyl, unsubstituted or substituted with one or moresubstituents independently selected from CH₃, —CF₃ and —N(CH₃)COCH₃.

In another aspect, also provided are compounds of formula (I), whereinR¹ is 3-pyridyl, substituted with one or more substituents independentlyselected from —CF₃ and —N(CH₃)COCH₃. In yet another aspect, alsoprovided are compounds of formula (I), wherein R¹ is pyrazinyl,substituted with —CH₃, —N(CH₃)₂, —NH(CH₃), or —N(CH₃)COCH₃. In stillanother aspect, also provided are compounds of formula (I), wherein R¹is unsubstituted pyrimidyl.

In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II),and (IIa), R² is substituted with one or more substituents Z, wherein Zis independently selected from halogen, CN, substituted or unsubstitutedC₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted 3-6 membered heterocyclyl, —NR(substituted orunsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂ or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl orsubstituted or unsubstituted C₅₋₆ heteroaryl. In some such embodiments,R² is substituted with one or more substituents independently selectedfrom Cl, F, Br, CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃,—CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F, —CHF₂, —CF₃; substituted orunsubstituted cycloalkyl selected from cyclopropyl, cyclobutyl, andcyclopentyl; substituted or unsubstituted heterocyclyl selected frompiperidyl, piperazinyl, morpholinyl and thiomorpholinyl;—NH(bicyclo[1.1.1]pentyl), —N(CH₃)(bicyclo[1.1.1]pentyl); —NHCO(CH₃),—N(CH₃)CO(CH₃), —NHCO(CH₂CH₃), —N(CH₃)CO(CH₂CH₃); —COOH, —COOCH₃;—SO₂CH₃, —SO₂CH₂CH₃; —SO₂NHCH₃, —SO₂N(CH₃)₂; —SO₂(aziridinyl),—SO₂(piperidyl), —SO₂(1-methyl-aziridinyl), —SO₂(1-methyl-piperidyl),—SO₂(1-cyclopropyl-piperidyl), —OR⁶, and —CON(R⁷)₂. In some suchembodiments, R⁶ is selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, difluorocyclobutyl, difluorocyclopentyl, —CH₂-cyclopropyl,—CH₂-cyclobutyl, oxetanyl, piperidyl, fluoropiperidyl,-(1-methyl-piperidyl), -(1-isopropyl-piperidyl),-(1-isopropyl-fluoropiperidyl), -(1-isopropyl-difluoropiperidyl),-(1-cyclopropyl-piperidyl), -(1-cyclobutyl-piperidyl),-(1-cyclopentyl-piperidyl), -(1-cyclopropyl-fluoropiperidyl),-(1-cyclopropyl-difluoropiperidyl), -(1-CH₂-cyclopropyl-piperidyl),-(1-acetyl-piperidyl), -(1-(COCH(CH₃)₂)-piperidyl), tetrahydrofuranyl,tetrahydropyranyl, -(2-methyl-2-azaspiro[3.3]heptyl),-(2-cyclopropyl-2-azaspiro[3.3]heptyl), and-(6-methyl-6-azaspiro[3.4]octyl). In some other such embodiments, R⁶ isselected from —CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)CH₂CH₃, —CHF₂, —CF₃,—CH₂CF₃, cyclopropyl, cyclohexyl, difluorocyclobutyl, —CH₂-cyclopropyl,oxetanyl, piperidyl, -(1-methyl-piperidyl),-(1-isopropyl-difluoropiperidyl), -(1-cyclopentyl-piperidyl),-(1-cyclopropyl-fluoropiperidyl), -(1-cyclopropyl-difluoropiperidyl),-(1-CH₂-cyclopropyl-piperidyl), -(1-acetyl-piperidyl),-(1-(COCH(CH₃)₂)-piperidyl), tetrahydropyranyl,-(2-methyl-2-azaspiro[3.3]heptyl),-(2-cyclopropyl-2-azaspiro[3.3]heptyl), and-(6-methyl-6-azaspiro[3.4]octyl). In yet other such embodiments, each R⁷is independently selected from H, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂, —CF₃,—CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃, or two R⁷ and the nitrogen to whichthey are attached form a heterocycle selected from unsubstituted orsubstituted pyrrolidyl, piperidyl, piperazinyl, or morpholinyl. In stillother embodiments, each R⁷ is independently selected from H, —CH₃, and—CH₂CF₃, or two R⁷ and the nitrogen to which they are attached form apyrrolidyl, 1-methyl-piperazinyl, or morpholinyl. In some suchembodiments, R^(N) is H, or substituted or unsubstituted C₁₋₅ alkyl. Insome such embodiments, R^(N) is —H, —CH₃, —CH₂CH₃, or —CH(CH₃)₂.

Also provided are compounds of formula (I), (Ia), (Ib), (Ic), (II), or(IIa), wherein R² is 2-pyridyl, substituted with one or moresubstituents Z, wherein Z is independently selected from halogen, CN,substituted or unsubstituted C₁₋₄ alkyl, substituted or unsubstitutedC₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 membered heterocyclyl,—NR(substituted or unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR,—SO₂(C₁₋₃ alkyl), —SO₂NR₂, —SO₂(substituted or unsubstitutedheterocyclyl), —OR⁶, and —CON(R⁷)₂, or two Z together with the carbonsto which they are attached form a substituted or unsubstituted 5-6membered heterocyclyl or substituted or unsubstituted C₅₋₆ heteroaryl.Also provided are compounds of formula (I), (Ia), (Ib), (Ic) (II), or(IIa), wherein R² is 2-pyridyl, substituted with one or moresubstituents independently selected from Cl, F, Br, CN, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F,—CHF₂, —CF₃; substituted or unsubstituted cycloalkyl selected fromcyclopropyl, cyclobutyl, and cyclopentyl; substituted or unsubstitutedheterocyclyl selected from piperidyl, piperazinyl, morpholinyl andthiomorpholinyl; —NH(bicyclo[1.1.1]pentyl),—N(CH₃)(bicyclo[1.1.1]pentyl); —NHCO(CH₃), —N(CH₃)CO(CH₃),—NHCO(CH₂CH₃), —N(CH₃)CO(CH₂CH₃); —COOH, —COOCH₃; —SO₂CH₃, —SO₂CH₂CH₃;—SO₂NHCH₃, —SO₂N(CH₃)₂; —SO₂(aziridinyl), —SO₂(piperidyl),—SO₂(1-methyl-aziridinyl), —SO₂(1-methyl-piperidyl),—SO₂(1-cyclopropyl-piperidyl), —OR⁶, and —CON(R⁷)₂. Also provided arecompounds of formula (I), (Ia), (Ib), (Ic), (II), or (IIa), wherein R²is 2-pyridyl, substituted with one or more substituents independentlyselected from F, CN, —CH₃, —CH(CH₃)₂, —CHF₂, —CF₃; -cyclopropyl;-(1-methyl-piperidyl), -(1-methyl-piperazinyl), thiomorpholinyl1,1-dioxidyl; —NH(bicyclo[1.1.1]pentyl); —NHCO(CH₃), —N(CH₃)CO(CH₃);—COOCH₃; —SO₂CH₃; —SO₂N(CH₃)₂; —SO₂(1-methyl-aziridinyl),—SO₂(1-methyl-piperidyl), —SO₂(1-cyclopropyl-piperidyl); —OCH₃,—OCH(CH₃)₂, —OC(CH₃)₃, —OCH(CH₃)CH₂CH₃, —OCHF₂, —OCF₃, —OCH₂CF₃,—O-cyclopropyl, —O-cyclohexyl, —O-difluorocyclobutyl,—O—(CH₂-cyclopropyl), —O-oxetanyl, —O-piperidyl,—O-(1-methyl-piperidyl), —O-(1-isopropyl-difluoropiperidyl),—O-(1-cyclopentyl-piperidyl), —O-(1-cyclopropyl-fluoropiperidyl),—O-(1-cyclopropyl-difluoropiperidyl), —O-(1-CH₂-cyclopropyl-piperidyl),—O-(1-acetyl-piperidyl), —O-(1-(COCH(CH₃)₂)-piperidyl),—O-tetrahydropyranyl, —O-(2-methyl-2-azaspiro[3.3]heptyl),—O-(2-cyclopropyl-2-azaspiro[3.3]heptyl),—O-(6-methyl-6-azaspiro[3.4]octyl); —CONH₂, —CON(CH₃)₂, —CONHCH₂CF₃,—CO(pyrrolidyl), —CO(1-methyl-piperazinyl), and —CO(morpholinyl).

In another aspect, provided are compounds of formula (Ia), wherein X isS and Y is N, and R² is 2-pyridyl, unsubstituted or substituted with oneor more substituents independently selected from F, CN, —CH₃, —CH(CH₃)₂,—CHF₂, —CF₃; cyclopropyl; -(1-methyl-piperidyl),-(1-methyl-piperazinyl), thiomorpholinyl 1,1-dioxidyl;—NH(bicyclo[1.1.1]pentyl); —NHCO(CH₃), —N(CH₃)CO(CH₃); —COOCH₃; —SO₂CH₃;—SO₂N(CH₃)₂; —SO₂(1-methyl-aziridinyl), —SO₂(1-methyl-piperidyl),—SO₂(1-cyclopropyl-piperidyl); —OCH₃, —OCH(CH₃)₂, —OCH(CH₃)CH₂CH₃,—OCF₃, —OCH₂CF₃, —O-cyclopropyl, —O-cyclohexyl, 0-difluorocyclobutyl,—O—(CH₂-cyclopropyl), —O-oxetanyl, —O-piperidyl,—O-(1-methyl-piperidyl), —O-(1-isopropyl-difluoropiperidyl),—O-(1-cyclopentyl-piperidyl), —O-(1-cyclopropyl-fluoropiperidyl),—O-(1-cyclopropyl-difluoropiperidyl), —O-(1-CH₂-cyclopropyl-piperidyl),—O-(1-acetyl-piperidyl), —O-(1-(COCH(CH₃)₂)-piperidyl),—O-tetrahydropyranyl, —O-(2-methyl-2-azaspiro[3.3]heptyl),—O-(2-cyclopropyl-2-azaspiro[3.3]heptyl),—O-(6-methyl-6-azaspiro[3.4]octyl); —CONH₂, —CON(CH₃)₂, —CONHCH₂CF₃,—CO(pyrrolidyl), —CO(1-methyl-piperazinyl), and —CO(morpholinyl).

In yet another aspect, provided are compounds of formula (Ib), wherein Xis N and Y is S, and R² is 2-pyridyl, unsubstituted or substituted withone or more substituents independently selected from —CH₃, —OCH₃,—OCH(CH₃)₂, —O-cyclohexyl, —O-(1-methyl-piperidyl), and—O-tetrahydropyranyl.

In still another aspect, provided are compounds of formula (Ia), whereinX is O and Y is N, and R² is 2-pyridyl, unsubstituted or substitutedwith one or more substituents independently selected from F, —CH₃,—OCH₃, —OCH(CH₃)₂, —O-oxetanyl, —O-cyclohexyl, —O-(1-methyl-piperidyl),—O-tetrahydropyranyl, and —CON(CH₃)₂.

In another aspect, provided are compounds of formula (Ib), wherein X isN and Y is O, and R² is 2-pyridyl, unsubstituted or substituted with oneor more substituents independently selected from —CH₃, —CH(CH₃)₂, —CF₃,—OCH₃, —OCH(CH₃)₂, —O-cyclohexyl, and —O-tetrahydropyranyl.

In another aspect, provided are compounds of formula (Ia), wherein X isNH and Y is N, and R² is 2-pyridyl, unsubstituted or substituted withone or more substituents independently selected from —OCH(CH₃)₂, and—O-(1-methyl-piperidyl).

In another aspect, also provided are compounds of formula (Ib), whereinX is N and Y is NH, and R² is 2-pyridyl, unsubstituted or substitutedwith one or more substituents independently selected from —CH₃, —OCH₃,and —O-tetrahydropyranyl.

In another aspect, provided are compounds of formula (Ic), wherein R is—CH₃, X is N and Y is N, and R² is 2-pyridyl, unsubstituted orsubstituted with one or more substituents independently selected from—OCH(CH₃)₂, and —O-cyclopropyl.

In another aspect, provided are compounds of formula (IIa), wherein Y isN and R² is 2-pyridyl, unsubstituted or substituted with one or moresubstituents independently selected from —CH₃, —O(C(CH₃)₃, and—O-tetrahydropyranyl.

In still another aspect, provided are compounds of formula (I), (Ia),(Ib), (Ic), (II), or (IIa), wherein R² is pyridazinyl, substituted with—OCH(CH₃)₂. In another aspect, provided are compounds of formula (I),(Ia), (Ib), (Ic), (II), or (Ia), wherein R² is pyrazinyl, substitutedwith —OCH₃, —OCH(CH₃)₂, or —OCH₂CH(CH₃)₂. In still another aspect,provided are compounds of formula (I), (Ia), (Ib), (Ic), (II), or (IIa),wherein R² is pyrimidyl, substituted with —OCH(CH₃)₂ or—O-(1-methyl-piperidyl).

Also provided are compounds of formula (I), (Ia), (Ib), (Ic), (II), or(IIa), wherein R² is 2-pyridyl substituted with two substituents Z,wherein the two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-membered heterocyclyl. In somesuch embodiments, the two Z together with the carbons to which they areattached form a substituted or unsubstituted dihydropyrolyl ordihydrofuryl.

Also provided are compounds of formula (I), (Ia), (Ib), (Ic), (II), or(IIa), wherein R² is 2-pyridyl substituted with two substituents Z,wherein the two Z together with the carbons to which they are attachedform a substituted or unsubstituted C₅₋₆ heteroaryl. In some otherembodiments, R² is a substituted or unsubstituted6,7-dihydro-5H-pyrrolo[3,4-b]pyridyl;2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl;2,3-dihydro-1H-pyrrolo[3,4-c]pyridyl;2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl; 1H-pyrrolo[2,3-c]pyridyl; or2,3-dihydrofuro[2,3-c]pyridyl. In some such embodiments, R² issubstituted with one or more substituents selected from —CH₃, —CH(CH₃)₂,—CH₂-cyclopropyl, and —COCH₃.

Also provided are compounds of formula (I), (Ia), (Ib), (Ic), (II), or(IIa), wherein R² is

wherein R^(2a) is H, —CH₃, —CH(CH₃)₂, —CH₂cyclopropyl, or —COCH₃, R^(2b)is —CH₃, R^(2c) is H or —CH₃ and X is O or NR. In some such embodiments,R is independently H, or —CH₃.

In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II),or (IIa) R^(N) is —H, —CH₃, —CH₂CH₃, or —CH(CH₃)₂. In other embodimentsof compounds of formula (I), (Ia), (Ib), (Ic), (II), or (IIa), each R isindependently H, or —CH₃.

In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II),or (IIa), R¹ is 2-pyridyl, 3-pyridyl or pyrazinyl, wherein R¹ isunsubstituted or substituted with one or more substituents independentlyselected from halogen, CN, substituted or unsubstituted C₁₋₄ alkyl,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted 3-6 membered heterocyclyl, substituted or unsubstitutedaryl, —NR₂, —COOR, —OR³, —SO₂NR₂, —SO₂(substituted or unsubstitutedheterocyclyl), —N(R)CO(R⁴), and —CON(R⁵)₂; and R² is 2-pyridyl,pyridazinyl, pyrazinyl or pyrimidyl, wherein R² is substituted with oneor more substituents Z, wherein Z is independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR(substituted or unsubstituted C₃₋₇ cycloalkyl),—N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl), —SO₂NR₂, —SO₂(substituted orunsubstituted heterocyclyl), —OR⁶, and —CON(R⁷)₂. In some suchembodiments, R^(N) is H, or substituted or unsubstituted C₁₋₅ alkyl. Insome such embodiments, R¹ is unsubstituted or substituted with one ormore substituents independently selected from F; CN; —CH₃, —CH(CH₃)₂,—C(CH₃)₃, —CHF₂, —CF₃; cyclopropyl, cyclopentyl; pyrrolidyl,pyrrolidinonyl, piperidyl, 1-methyl-piperidyl, piperazinyl, piperazinylsubstituted with —COCH₃ or —(COCH₂CF₃), morpholinyl; phenyl; —NHCH₃,—N(CH₃)₂; —COOMe; —OCH₃, —OCH(CH₃)₂, —O— piperidyl,—O-tetrahydropyranyl, —O-(1-methyl-piperidyl); —SO₂N(CH₃)₂;—SO₂(aziridinyl), —NHCOCH₃, —N(CH₃)COCH₃, —N(CH(CH₃)₂)COCH₃,—N(CH₃)CO(CH(CH₃)₂), —N(CH₃)CO(cyclopropyl), —N(CH₃)CO(cyclobutyl),—N(CH₃)CO(cyclopentyl); —CONH₂, —CONHCH₃, —CON(CH₃)₂,—CON(CH₃)cyclopropyl, —CONH(difluorocyclobutyl),—CON(CH₃)(difluorocyclobutyl), —CONH(CH₂-cyclopropyl), and—CO(pyrrolidyl); and R² is substituted with one or more substituentsindependently selected from F, CN, —CH₃, —CH(CH₃)₂, —CHF₂, —CF₃;-cyclopropyl; -(1-methyl-piperidyl), -(1-methyl-piperazinyl),thiomorpholinyl 1,1-dioxidyl; —NH(bicyclo[1.1.1]pentyl); —NHCO(CH₃),—N(CH₃)CO(CH₃); —COOCH₃; —SO₂CH₃; —SO₂N(CH₃)₂;—SO₂(1-methyl-aziridinyl), —SO₂(1-methyl-piperidyl),—SO₂(1-cyclopropyl-piperidyl); —OCH₃, —OCH(CH₃)₂, —OCH(CH₃)CH₂CH₃,—OCHF₂, —OCF₃, —OCH₂CF₃, —O-cyclopropyl, —O-cyclohexyl,—O-difluorocyclobutyl, —O—(CH₂-cyclopropyl), —O-oxetanyl, —O-piperidyl,—O-(1-methyl-piperidyl), —O-(1-isopropyl-difluoropiperidyl),—O-(1-cyclopentyl-piperidyl), —O-(1-cyclopropyl-fluoropiperidyl),—O-(1-cyclopropyl-difluoropiperidyl), —O-(1-CH₂-cyclopropyl-piperidyl),—O-(1-acetyl-piperidyl), —O-(1-(COCH(CH₃)₂)-piperidyl),—O-tetrahydropyranyl, —O-(2-methyl-2-azaspiro[3.3]heptyl),—O-(2-cyclopropyl-2-azaspiro[3.3]heptyl),—O-(6-methyl-6-azaspiro[3.4]octyl); —CONH₂, —CON(CH₃)₂, —CONHCH₂CF₃,—CO(pyrrolidyl), —CO(1-methyl-piperazinyl), and —CO(morpholinyl). Insome such embodiments, R^(N) is —H, —CH₃, —CH₂CH₃, or —CH(CH₃)₂. In someembodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II), or(IIa), R¹ is 2-pyridyl, substituted with one or more substituentsindependently selected from —CH₃, —CF₃, —C(CH₃)₃, pyrrolidyl,pyrrolidinonyl, —N(CH₃)CO(CH₃), —N(CH₃)CO(cyclopropyl), —SO₂N(CH₃)₂ and—SO₂(aziridinyl); and R² is 2-pyridyl, substituted with one or moresubstituents selected from —CF₃, —OCH(CH₃)₂, and —OC(CH₃)₃; or R² is2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, substituted with —CH₃, or—CH(CH₃)₂. In some such embodiments, R^(N) is —H.

In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II),or (IIa), R¹ is pyrazinyl, substituted with one or more substituentsselected from NHCH₃ and N(CH₃)COCH₃; and R² is1H-pyrrolo[2,3-c]pyridine, substituted with —CH(CH₃)₂.

In some embodiments of compounds of formula (I), (Ia), (Ib), (Ic), (II),or (IIa), R¹ is 2-pyridyl substituted with one or more substituentsindependently selected from —CF₃, —N(CH₃)COCH₃ and —CON(CH₃)₂; and R² is2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine, substituted with —CH₃.

Further embodiments provided herein include combinations of at least oneof the particular embodiments set forth above.

Representative compounds of formula (I), formula (Ia), formula (Ib),formula (Ic), formula (II), and formula (IIa) are set forth in Table 1.

Each of the compounds in Table 1 was tested in one or more of the invitro parasite motility assays and was found to have activity therein.

Methods for Making Compounds

The Heterocyclic Compounds of formula (I), (Ia), (Ib), (Ic), (II), or(IIa), and Table 1, can be made using conventional organic syntheses andcommercially available starting materials. By way of example and notlimitation, Heterocyclic Compounds of formula (I), (Ia), (Ib), (Ic),(II), or (IIa), and Table 1, can be prepared as outlined in Scheme 1,shown below, as well as in the examples set forth herein. It should benoted that one skilled in the art would know how to modify theprocedures set forth in the illustrative schemes and examples to arriveat the desired products.

As shown in Scheme 1, compounds of formula (Ia) wherein X is S and Y isN, and R¹, R² and R^(N) are as defined herein, can be prepared startingfrom an appropriately derivatized imidamide (B) and isothiocyanates (D)(wherein X is S) or carbamothioate (D′). Imidamides (B) are commerciallyavailable or may be prepared according to known methods (see forexample, J. Med. Chem. (2016), 59, 965-984). Treatment of appropriatelysubstituted nitriles (A) with NH₄Cl in the presence of a base, such assodium methoxide, in a solvent, such as MeOH, and heating attemperatures ranging from about 15 to about 70° C. provides imidamides(B). Isothiocyanates (D) are commercially available or may be preparedaccording to known methods (see for example, J. Org. Chem. (2017), 82,5898-5903). Reaction of appropriately substituted amines (C) whereinR^(N) is H, with thiophosgene, optionally in the presence of a base,such as DIPEA, in a solvent, such as DCM, at temperatures ranging fromabout −5 to about 20° C. provides isothiocyanates (D). Compounds offormula (Ia) wherein R^(N) is H, are obtained by the combination ofimidamides (B) and isothiocyanates (D) in a solvent, such as DCM oracetone, in the presence of a base, such as TEA, and heating attemperatures ranging from about 15 to about 70° C., and subsequentcyclization with 12 and oxidation with hydrogen peroxide in a solvent,such as EtOH, at temperatures ranging from about 0 to about 25° C. orcyclization by treatment with diisopropyl azodiformate in a solvent,such as THF, at temperatures ranging from about 0 to about 25° C. Amines(C) wherein R^(N) is substituted or unsubstituted C₁₋₅ alkyl arecommercially available or may be prepared by alkylation of amine (C)wherein R^(N) is H with R^(N)—I, in a solvent, such as THF, in thepresence of a base, such as n-BuLi, at temperatures ranging from about 0to about 25° C. Carbamothioate (D′) may be prepared by reaction ofappropriately substituted amines (C), wherein R^(N) is substituted orunsubstituted C₁₋₅ alkyl, with O-phenyl carbonochloridothioate in asolvent, such as THF, in the presence of a base, such as potassiumcarbonate, at temperatures ranging from about 0 to about 25° C.Compounds of formula (Ia) wherein R^(N) is substituted or unsubstitutedC₁₋₅ alkyl, are obtained by the combination of imidamides (B) andcarbamothioate (D′) in a solvent, such as DMSO, in the presence of base,such as potassium tert-butoxide, at temperatures ranging from about 0 toabout 25° C. Subsequent alkylation of the latter compound with R^(N)—I,in a solvent, such as DMF, in the presence of a base, such as potassiumcarbonate, at room temperature, provided the compounds of formula (Ia),wherein X is S and Y is N, and R^(N) is substituted or unsubstitutedC₁₋₅ alkyl.

Alternatively, as shown in Scheme 2, compounds of formula (Ia) wherein Xis O, Y is N and R¹, R² and R^(N) are as defined herein, can be preparedstarting from an appropriately derivatized trichloromethyl-oxadiazole(F) and amine (C). Trichloromethyl-oxadiazole (F) can be prepared fromappropriately substituted N-hydroxyimidamides (E), which arecommercially available or may be prepared according to known methods.For example treatment of appropriately substituted nitriles (A) withhydroxylamine hydrochloride in the presence of a base, such as TEA, in asolvent, such as EtOH, and heating at temperatures of about 70° C.,provides the N-hydroxyimidamides (E). Treatment of N-hydroxyimidamides(E) with 2,2,2-trichloroacetic anhydride in a solvent, such as toluene,at a temperature of about 110° C., provides trichloromethyl-oxadiazoles(F). SN-aryl substitution reaction of trichloromethyl-oxadiazole (F)with R¹NH₂ (C) in in the presence of a base, such as NaH, in a solvent,such as THF, and heating at temperatures ranging from about 0 to about25° C., provides compounds of formula (Ia), wherein X is O, and Y is N.

As shown in Scheme 3, compounds of formula (Ib) wherein X is N, Y is Sor O, R is H, and R¹, R² and R^(N) are as defined herein, can beprepared starting from an appropriately derivatized hydrazide (H) andisothiocyanates (J), wherein Y is S. Hydrazides (H) and isothiocyanates(J) are commercially available or may be prepared according to knownmethods (see, for example, J. American Chemical Society (2015), 137(47),14982-14991) and those described herein. Esterification of appropriatelysubstituted carboxylic acids (G), for example by treatment with SOCl₂ ina solvent, such as MeOH, and heating at temperatures ranging from about10 to about 70° C., provides the ester derivative, which is subsequentlytransformed to hydrazide (H), wherein R is H, by treatment withhydrazine hydrate in a solvent, such as MeOH, and heating attemperatures ranging from room temperature to about 80° C. Compounds offormula (Ib), wherein X is N, Y is S and R^(N) is H, are obtained byreaction of the derivatized hydrazides (H) and isothiocyanates (J) in asolvent, such as DCM, and heating at temperatures of about 30° C.,followed by treatment with an acid, for example, p-toluenesulfonic acid,in a solvent, such as toluene, and heating at elevated temperatures,such as at about 100° C. Compounds of formula (Ib), wherein X is N, Y isO and R^(N) is H, are obtained by reaction of the derivatized hydrazides(H) and isothiocyanates (J) in a solvent, such as DCM, and heating attemperatures of about 30° C., followed by cyclization with either1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in a solvent, such asDMSO, and heating at temperatures of about 60° C., or by cyclizationwith 2-iodylbenzoic acid in the presence of base, such astrimethylamine, at temperatures of about 0° C.

As shown in Scheme 4, compounds of formula (Ic), wherein X and Y are N,R^(N) is H or substituted or unsubstituted C₁₋₄ alkyl, and R, R¹, R² areas defined herein, can be prepared starting from an appropriatelyderivatized hydrazide (H) and carbamimidothioate (L). Hydrazides (H) arecommercially available or when R is H, may be prepared according toknown methods, as described above. Hydrazides (H), wherein R issubstituted or unsubstituted C₁₋₄ alkyl, may be prepared by treatment ofappropriately substituted carboxylic acids (G) with appropriatelyN-substituted tert-butyl aminocarbamate in a solvent, such as DCM, inthe presence of a base, such as DIPEA, and coupling reagents, such ashydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride, at temperatures ranging from about 0 to about 25° C.Carbamimidothioate (L) are commercially available or may be preparedaccording to known methods from appropriately substitutedisothiocyanates (K). Treatment of isothiocyanates (K) with ammoniumhydroxide in a solvent, such as DCM, at ambient temperature provides thethiourea derivative, which upon alkylation with iodomethane in asolvent, such as ACN, and heating at temperatures ranging from roomtemperature to about 40° C., provides carbamimidothioate (L). Treatmentof hydrazide (H) and carbamimidothioate (L) in the presence of a base,such a pyridine or NaOH, and heating at temperatures ranging from about100 to about 160° C., provides compounds of formula (Ic), wherein X andY are N, and R^(N) is H. Alternatively, compounds of formula (Ic),wherein X and Y are N, and R^(N) is H, can be obtained by SN-arylsubstitution reaction with triazole (N). Treatment of the appropriatelysubstituted hydrazide (H) with methylisothiourea in the presence of anacid, such as sulfuric acid, in a solvent, such as H₂O, and heating attemperatures up to about 100° C., provides hydrazinecarboximidamide (M).Upon subsequent treatment with a base, such as pyridine or NaOH, andheating at temperatures ranging from about 100 to about 160° C. providesthe triazole derivative (N). Triazole derivative (N) is furtherelaborated by SN-aryl substitution with R¹-Hal, wherein Hal is halogen,for example F, in the presence of a base, such as NaH, in a solvent,such as DMF, and heating at temperatures ranging from about 0 to about25° C., to provide compounds of formula (Ic), wherein X and Y are N, andR^(N) is H.

As shown in Scheme 5, compounds of formula (IIa) wherein Y is N, and R¹,R² and R^(N) are as defined herein, can be prepared via two crosscoupling reactions with a 3,5-dihalogenated-1,2,4-thiadiazole (P),wherein Hal is halogen, appropriately substituted amine (C) andorganometallic compound (O). 3,5-Dihalogenated-1,2,4-thiadiazole (P) iscommercially available. Organometallic compound (O) are commerciallyavailable or may be prepared by known methods (see for example, J. Med.Chem. (2015) 48(16), 5096-5099). Treatment of3,5-dihalogenated-1,2,4-thiadiazole (P), wherein Hal is either Cl or Br,with appropriately substituted organometallic compound (O) in thepresence of a metal catalyst and ligand, such as Pd (PPh₃)₄ andcopper(I) thiophene-2-carboxylate, in a solvent, such as 1,4-dioxane attemperatures ranging from about 0 to about 20° C. followed by subsequenttreatment with amine (C) in the presence of metal catalyst and ligand,such as Pd₂(dba)₃ and Xantphos and in a solvent, such as 1,4-dioxane attemperatures ranging from about 20 to about 110° C. provides compoundsof formula (IIa) wherein Y is N.

In one aspect, provided herein are methods for preparing a HeterocyclicCompound of formula (Ia):

wherein X is S, Y is N, and R^(N) is substituted or unsubstituted C₁₋₅alkyl,

the methods comprising contacting a Heterocyclic Compound of formula(Ia)

wherein R^(N) is H,

with R^(N)—I, wherein R^(N) is substituted or unsubstituted C₁₋₅ alkyl,in a solvent, in the presence of a base, under conditions suitable toprovide a Heterocyclic Compound of formula (Ia); wherein

X is S;

Y is N;

R^(N) is substituted or unsubstituted C₁₋₅ alkyl;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —N(R)CO(R⁴), —CON(R⁵)₂, and substitutedor unsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached for a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached for a substituted or unsubstituted 3 to 6 memberedheterocyclyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In some such embodiments, the solvent is DMF. In some embodiments, thebase is potassium carbonate. In some embodiments, the contacting isperformed at room temperature.

In some embodiments, the methods further comprise preparing aHeterocyclic Compound of formula (Ia):

wherein X is S, Y is N, and R^(N) is H,

the methods comprising:

a) contacting a compound of formula (B):

with R¹—NCX, wherein X is S, in a first solvent, optionally in thepresence of a base;

b) contacting the product of step a) with 12 and hydrogen peroxide, in asecond solvent; under conditions suitable to provide a HeterocyclicCompound of formula (Ia), wherein R^(N) is H.

In some embodiments, the base is TEA. In some embodiments, the firstsolvent is DCM, acetone, or a mixture thereof. In some embodiments, thecontacting in step (a) is performed at a temperature ranging from about15 to about 70° C.

In some embodiments, the second solvent is EtOH. In some embodiments,the contacting in step (b) is performed at a temperature ranging fromabout 0 to about 25° C.

In some other embodiments, the methods further comprise preparing aHeterocyclic Compound of formula (Ia):

wherein X is S, Y is N, and R^(N) is H, the methods comprising:

a) contacting a compound of formula (B):

with R¹—NCX, wherein X is S, in a first solvent, optionally in thepresence of a base;

b) contacting the product of step a) with diisopropyl azodiformate, in asecond solvent, under conditions suitable to provide a HeterocyclicCompound of formula (Ia), wherein R^(N) is H.

In some embodiments, the base is TEA. In some embodiments, the firstsolvent is DCM, acetone, or a mixture thereof. In some embodiments, thecontacting in step (a) is performed at a temperature ranging from about15 to about 70° C.

In some embodiments, the second solvent is THF. In some embodiments, thecontacting in step (b) is performed at a temperature ranging from about0 to about 25° C.

In some embodiments, the methods further comprise preparing a compoundof formula (B):

the method comprising contacting R²—CN with NH₄Cl in the presence of abase, in a solvent, under conditions suitable to provide a compound offormula (B).

In one embodiment, the base is sodium methoxide. In one embodiment, thesolvent is MeOH. In some embodiments, the contacting is performed at atemperature ranging from 15 to 70° C.

In some embodiments, the methods further comprise preparing a compoundof formula (D):

R¹—N═C═X   (D)

wherein X is S, the method comprising contacting R¹NH₂ withthiophosgene, optionally in the presence of a base, in a solvent, underconditions suitable to provide a compound of formula (D) wherein X is S.

In one embodiment, the base is DIPEA. In one embodiment, the solvent isDCM. In some embodiments, the contacting is performed at a temperatureranging from −5 to 20° C.

In another aspect, provided herein are methods for preparing aHeterocyclic Compound of formula (Ia):

wherein X is O, and Y is N,

the methods comprising contacting a compound of formula (F)

with NHR¹R^(N), in a solvent, in the presence of a base, underconditions suitable to provide a Heterocyclic Compound of formula (Ia);wherein

X is O;

Y is N;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —N(R)CO(R⁴), —CON(R⁵)₂, and substitutedor unsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached for a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached for a substituted or unsubstituted 3 to 6 memberedheterocyclyl;

R^(N) is H, or substituted or unsubstituted C₁₋₅ alkyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In some such embodiments, the solvent is THF. In some embodiments, thebase is NaH. In some embodiments, the contacting is performed attemperatures ranging from about 0 to about 25° C.

In some embodiments, the methods further comprise preparing a compoundof formula (F)

the methods comprising contacting N-hydroxyimidamides of formula (E)

with 2,2,2-trichloroacetic anhydride in a solvent, under conditionssuitable to provide a a compound of formula (F).

In one embodiment, the solvent is toluene. In another embodiment, thecontacting is performed at a temperature of about 110° C.

In some embodiments, the methods further comprise preparing a compoundof formula (E)

the methods comprising contacting R²CN with hydroxylamine hydrochloridein the presence of a base, such as TEA, in a solvent, and heating attemperatures of about 70° C., under conditions suitable to provide a acompound of formula (E).

In one embodiment, the base is TEA. In one embodiment, the solvent isEtOH. In another embodiment, the contacting is performed at atemperature of about 70° C.

In one aspect, also provided herein are methods for preparing aHeterocyclic Compound of formula (Ib):

wherein X is N, Y is O, and R^(N) is H,

the methods comprising contacting a compound of formula (H)

with a compound of formula (J)

R¹—N═C═Y   (J)

wherein Y is S, in a solvent, at a first temperature, followed bycyclization with 2-iodylbenzoic acid in the presence of a base, at asecond temperature, under conditions suitable to provide a HeterocyclicCompound of formula (Ib); wherein

X is N;

Y is O;

R^(N) is H;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —N(R)CO(R⁴), —CON(R⁵)₂, and substitutedor unsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached for a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached for a substituted or unsubstituted 3 to 6 memberedheterocyclyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In some such embodiments, the solvent is DCM. In some embodiments, thecontacting is performed at a temperature of about 30° C. In someembodiments, the base is potassium carbonate. In some embodiments, thesecond temperature is about 0° C.

In one aspect, also provided herein are methods for preparing aHeterocyclic Compound of formula (Ib):

wherein X is N, Y is O, and R^(N) is H,

the methods comprising contacting a compound of formula (H)

with a compound of formula (J)

R¹—N═C═Y   (J)

wherein Y is S, in a solvent, at a first temperature, followed bycyclization with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in asecond solvent, at a second temperature, under conditions suitable toprovide a Heterocyclic Compound of formula (Ib); wherein

X is N;

Y is O;

R^(N) is H;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —N(R)CO(R⁴), —CON(R⁵)₂, and substitutedor unsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached for a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached for a substituted or unsubstituted 3 to 6 memberedheterocyclyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In some such embodiments, the solvent is DCM. In some embodiments, thecontacting is performed at a temperature of about 30° C. In someembodiments, the second solvent is DMSO. In some embodiments, the secondtemperature is about 60° C.

In some embodiments, the methods further comprise preparing a compoundof formula (Ib):

wherein X is N, Y is S, and R^(N) is H, the methods comprising:

a) contacting a compound of formula (H)

with a compound of formula (J)

R¹—N═C═Y   (J)

wherein Y is S, in a first solvent;

b) contacting the product of step a) with an acid, in a second solvent,under conditions suitable to provide a Heterocyclic Compound of formula(Ib), wherein X is N, Y is S, and R^(N) is H.

In some embodiments, the first solvent is DCM. In some embodiments, thecontacting in step (a) is performed at a temperature ranging of about30° C.

In some embodiments, the second solvent is toluene. In some embodimentsthe acid is p-toluenesulfonic acid. In some embodiments, the contactingin step (b) is performed at elevated temperature. In one embodiment, thecontacting in step (b) is performed at a temperature of about 100° C.

In some embodiments, the methods further comprise preparing a compoundof formula (H):

wherein R is H,

the methods comprising:

a) contacting R²COOH with SOCl₂, in a first solvent; and

b) contacting the product of step a) with hydrazine hydrate, in a secondsolvent under conditions suitable to provide a compound of formula (H),wherein R is H.

In some embodiments, the first solvent is MeOH. In one embodiment, thecontacting in step a) is performed at a temperature ranging from about10 to about 70° C.

In some embodiments, the second solvent is MeOH. In one embodiment, thecontacting in step b) is performed at a temperature ranging from roomtemperature to about 80° C.

In one aspect, provided herein are methods for preparing a HeterocyclicCompound of formula (Ic):

wherein X and Y are N, R^(N) is H,

the methods comprising contacting a compound of formula (H):

with a compound of formula (L):

in a solvent, in the presence of a base, under conditions suitable toprovide a Heterocyclic Compound of formula (Ic), wherein

X is N;

Y is N;

R^(N) is H;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —N(R)CO(R⁴), —CON(R⁵)₂, and substitutedor unsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached for a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached for a substituted or unsubstituted 3 to 6 memberedheterocyclyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In some embodiments, the base is pyridine or NaOH. In some embodiments,the contacting is performed at a temperature ranging from about 100 toabout 160° C.

In some embodiments, the methods further comprise preparing a compoundof formula (D):

the methods comprising:

a) contacting R¹—NCS with ammonium hydroxide in a first solvent; and

b) contacting the product of step a) with iodomethane, in a secondsolvent, under conditions suitable to provide a compound of formula (L).

In some embodiments, the first solvent is DCM. In one embodiment, thecontacting in step a) is performed at room temperature.

In some embodiments, the second solvent is MeCN. In one embodiment, thecontacting in step b) is performed at a temperature ranging from roomtemperature to about 40° C.

In one aspect, provided herein are methods for preparing a HeterocyclicCompound of formula (Ic):

X and Y are N, and R^(N) is H,

the methods comprising contacting a compound of formula (N):

with R¹-Hal, wherein Hal is F, in the presence of a base, in a solvent,under conditions suitable to provide a Heterocyclic Compound of formula(Ic), wherein

X is N;

Y is N;

R^(N) is H;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —N(R)CO(R⁴), —CON(R⁵)₂ and substitutedor unsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached for a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached for a substituted or unsubstituted 3 to 6 memberedheterocyclyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In some embodiments, the base is NaH. In some embodiments, the solventis DMF. In some embodiments, the contacting is performed at atemperature ranging from about 0 to about 25° C.

In some other embodiments, the methods further comprise preparing aHeterocyclic Compound of formula (IIa):

Y is N, and R^(N) is H,

the methods comprising contacting a compound of formula (P):

with NHR¹R^(N), in a solvent, in the presence of a metal catalyst andligand, in a solvent, under conditions suitable to provide aHeterocyclic Compound of formula (IIa), wherein

Y is N;

R^(N) is H;

R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl, each unsubstitutedor substituted with one or more substituents independently selected fromhalogen, CN, substituted or unsubstituted C₁₋₄ alkyl, substituted orunsubstituted C₃₋₇ cycloalkyl, substituted or unsubstituted 3-6 memberedheterocyclyl, —NR₂, —COOR, —OR³, —N(R)CO(R⁴), —CON(R⁵)₂, and substitutedor unsubstituted C₆₋₁₀ aryl;

R² is

each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl;

Each R³ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted 3-6 membered heterocyclyl;

Each R⁴ is independently selected from substituted or unsubstituted C₁₋₅alkyl, or substituted or unsubstituted C₃₋₆ cycloalkyl;

Each R⁵ is independently selected from H, substituted or unsubstitutedC₁₋₅ alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, andsubstituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆ cycloalkyl), or two R⁵and the nitrogen to which they are attached for a substituted orunsubstituted 3 to 6 membered heterocyclyl;

Each R⁶ is independently selected from substituted or unsubstituted C₁₋₅alkyl, substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃alkyl)(substituted or unsubstituted C₃₋₆ cycloalkyl), or substituted orunsubstituted 3-8 membered heterocyclyl;

Each R⁷ is independently selected from H, and substituted orunsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen to which they areattached for a substituted or unsubstituted 3 to 6 memberedheterocyclyl; and

each R is independently selected from H and substituted or unsubstitutedC₁₋₄ alkyl;

provided R¹ and R² are not both unsubstituted.

In some such embodiments, the solvent is 1,4-dioxane. In someembodiments, the catalyst and ligand is Pd (PPh₃)₄ and copper(I)thiophene-2-carboxylate. In some embodiments the second catalyst andligand is Pd₂(dba)₃ and Xantphos. In some embodiments, the contacting isperformed at temperatures ranging from about 10 to about 110° C.

In some embodiments, the methods further comprise preparing a compoundof formula (N):

the methods comprising contacting a compound of formula (M):

with a base, in a solvent, under conditions suitable to provide acompound of formula (N).

In some embodiments, the base is pyridine or NaOH. In some embodiments,the solvent is H₂O. In some embodiments, the contacting is performed ata temperature ranging from about 100 to about 160° C.

In some embodiments, the methods further comprise preparing a compoundof formula (M):

the methods comprising contacting a compound of formula (H):

with methylisothiourea in presence of an acid, in a solvent, underconditions suitable to provide a compound of formula (M).

In some embodiments, the acid is sulfuric acid. In some embodiments, thesolvent is H₂O. In some embodiments, the contacting is performed at atemperature ranging from room temperature to about 100° C.

In some embodiments, the methods further comprise preparing a compoundof formula (H)

wherein R is substituted or unsubstituted C₁₋₄ alkyl,

the methods comprising contacting R²COOH with

in a solvent, in the presence of a base and a coupling reagent, underconditions suitable to provide a compound of formula (H), wherein R issubstituted or unsubstituted C₁₋₄ alkyl.

In one embodiment, the solvent is DCM. In another embodiment, the baseis DIPEA. In other embodiments, the coupling agent ishydroxybenzotriazole and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride. In some embodiments, the contacting is performed at atemperature from about 0 to about 25° C.

Methods of Use

The Heterocyclic Compounds, including compounds of formula (I), (Ia),(Ib), (Ic), (II), (IIa), and Table 1 have utility as pharmaceuticals totreat, prevent or improve conditions in animals and humans. TheHeterocyclic Compounds provided herein have utility for use in thetreatment or prevention of all diseases, disorders or conditionsdisclosed herein.

In one aspect, provided herein is a method of treating a disease causedby a helminthic infection. In certain embodiments, a compound asdescribed herein is used in human medical therapy, particularly in thetreatment of helminthic infection. In certain embodiments, a compound asprovided herein is used in animal medical therapy, particularly in thetreatment of helminthic infections. In certain embodiments, the methodincludes administering a therapeutically effective amount of a compoundas described to a subject having a disease caused by a helminthicinfection.

In one aspect, provided herein is a method of treating a disease causedby a filarial worm infection. In certain embodiments, a compound asdescribed herein is used in human medical therapy, particularly in thetreatment of filarial worm infection. In certain embodiments, a compoundas provided herein is used in animal medical therapy, particularly inthe treatment of filarial worm infections. In certain embodiments, themethod includes administering a therapeutically effective amount of acompound as described to a subject having a disease caused by a filarialworm infection.

In one embodiment, provided herein is a method for the treatment orprevention of helminthic infections and diseases, the methods comprisingadministering to a subject an effective amount of a HeterocyclicCompound, or a pharmaceutically acceptable salt, tautomer, isotopologue,or stereoisomer thereof. In some such embodiments, the helminthicinfection is a filarial worm infection.

In one aspect, provided herein is a method of treating a disease causedby helminthic infection. In certain embodiments, a HeterocyclicCompound, or a pharmaceutically acceptable salt, tautomer, isotopologue,or stereoisomer thereof, is used in human medical therapy, particularlyin the treatment of helminthic infections. In certain embodiments, aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, is used in animal medicaltherapy, particularly in the treatment of helminthic infections. Incertain embodiments, the method includes administering a therapeuticallyeffective amount of a Heterocyclic Compound, or a pharmaceuticallyacceptable salt, tautomer, isotopologue, or stereoisomer thereof, to asubject having a disease caused by helminthic infection.

In one embodiment, provided herein is a method for the treatment orprevention of filarial worm infections and diseases, the methodscomprising administering to a subject an effective amount of aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof.

In one aspect, provided herein is a method of treating a disease causedby a filarial worm infection. In certain embodiments, a HeterocyclicCompound, or a pharmaceutically acceptable salt, tautomer, isotopologue,or stereoisomer thereof, is used in human medical therapy, particularlyin the treatment of a filarial worm infections. In certain embodiments,a Heterocyclic Compound, or a pharmaceutically acceptable salt,tautomer, isotopologue, or stereoisomer thereof, is used in animalmedical therapy, particularly in the treatment of of a filarial worminfection. In certain embodiments, the method includes administering atherapeutically effective amount of a Heterocyclic Compound, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, to a subject having a disease caused by a filarialworm infection.

In another aspect, also provided is a method of preventing a diseasecaused by helminthic infection. In certain embodiments, a HeterocyclicCompound, or a pharmaceutically acceptable salt, tautomer, isotopologue,or stereoisomer thereof, is used in human medical therapy, particularlyin the prevention of helminthic infection. In certain embodiments, aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, is used in animal medicaltherapy, particularly in the prevention of helminthic infection. Incertain embodiments, the method includes administering a therapeuticallyeffective amount of a Heterocyclic Compound, or a pharmaceuticallyacceptable salt, tautomer, isotopologue, or stereoisomer thereof, to asubject to prevent a disease caused by helminthic infection.

In another aspect, also provided is a method of preventing a diseasecaused by a filarial worm infection. In certain embodiments, aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, is used in human medical therapy,particularly in the prevention of a filarial worm infection. In certainembodiments, a Heterocyclic Compound, or a pharmaceutically acceptablesalt, tautomer, isotopologue, or stereoisomer thereof, is used in animalmedical therapy, particularly in the prevention of a filarial worminfection. In certain embodiments, the method includes administering atherapeutically effective amount of a Heterocyclic Compound, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, to a subject to prevent a disease caused by afilarial worm infection.

In another aspect, provided herein is a method of treating or preventinga parasitic disease. In certain embodiments, the parasitic disease isassociated with a worm. In certain embodiments, the parasitic disease iscaused by a worm. In certain embodiments, the parasitic worm iscategorized as cestode (tapeworm), nematode (roundworm) and trematode(flatworm or fluke). In certain embodiments, the parasitic disease isassociated with a helminth. In certain embodiments, the parasiticdisease is associated with a nematode. In certain embodiments, thenematode is Wuchereria bancrofti. In certain embodiments, the nematodeis Brugia malayi. In certain embodiments, the nematode is Brugia timori.In certain embodiments, the nematode is Onchocerca volvulus. In certainembodiments, the nematode is Dirofilaria immitis. In some embodiments,the nematode is Haemonchus contortus. In certain embodiments, thenematode is Ascaris lumbricoides. In certain embodiments, the nematodeis Necator americanus. In still another embodiments, the nematode isAncylostoma duodenale. In yet other embodiments, the nematode isTrichuris trichiura. In certain embodiments, the parasitic disease isassociated with a trematode. In certain embodiments, the parasiticdisease is associated with Schistosoma. In certain embodiments, theparasitic disease is associated with Schistosoma mansoni. In certainembodiments, the parasitic disease is enterobiasis, oxyuriasis,ascariasis, ancylostomiasis, necatoriasis, dracunculiasis, filariasis,onchocerciasis, schistosomiasis, or trichuriasis. In certainembodiments, the parasitic disease is schistosomiasis. In certainembodiments, the parasitic disease is urinary schistosomiasis. Incertain embodiments, the parasitic disease is intestinalschistosomiasis. In certain embodiments, the parasitic disease is Asianintestinal schistosomiasis. In certain embodiments, the parasiticdisease is visceral schistosomiasis. In certain embodiments, theparasitic disease is acute schistosomiasis. In certain embodiments, theparasitic disease is lymphatic filariasis. In certain embodiments, theparasitic disease is bancroftian filariasis. In certain embodiments, theparasitic disease is subcutaneous filariasis. In certain embodiments,the parasitic disease is serious cavity filariasis. In certainembodiments, the parasitic disease is elephantiasis. In certainembodiments, the parasitic disease is elephantiasis tropica. In certainembodiments, the parasitic disease is onchocerciasis. In certainembodiments, the dirofilariasis is dirofilariasis in dogs. In someembodiments, the dirofilariasis is caused by Dirofilaria immitis orDirofilaria repens. In certain embodiments, the parasitic disease ishaemonchosis. In certain embodiments, the haemonchosis is haemonchosisin sheep and goats. In some embodiments, the haemonchosis is caused byHaemonchus contortus.

In certain aspects, the present methods comprise a step of administeringa Heterocyclic Compound, or a pharmaceutically acceptable salt,tautomer, isotopologue, or stereoisomer thereof, to a subject. Incertain embodiments, the methods comprise administering a HeterocyclicCompound, or a pharmaceutically acceptable salt, tautomer, isotopologue,or stereoisomer thereof, to a subject for no more than fourteen (14)days. In certain embodiments, the methods comprise administering aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, to a subject for no more thanseven (7) days. In certain embodiments, the subject is in need oftreatment for an helminthic infection. In certain embodiments, thesubject is in need of treatment for a filarial infection. In certainembodiments, the subject has an helminthic infection. In certainembodiments, the subject is at risk for having an helminthic infection.In certain embodiments, the subject has a filarial infection. In certainembodiments, the subject is at risk for having a filarial infection. Incertain embodiments, the subject is a pediatric subject. In certainembodiments, the subject is less than nine (9) years of age. In certainembodiments, the subject is less than eight (8) years of age. In certainembodiments, the subject is a pregnant woman. In certain embodiments,the subject is a post-partum woman. In certain embodiments, the subjectis a woman of childbearing potential. In certain embodiments, thesubject is an individual attempting to conceive a child. In certainembodiments, the subject is a domestic animal. In certain embodiments,the subject is a dog.

The compounds disclosed herein exhibit potency against helminths, and,therefore, have the potential to kill and/or inhibit the growth, molt,or motility of such helminths. The compounds disclosed herein exhibitpotency against filarial worms, and, therefore, have the potential tokill and/or inhibit the molt, or motility of such filarial worms. Thus,in one aspect provided is a method of killing a filarial worm,comprising: contacting the filarial worm with a Heterocyclic Compound,or a pharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, in an amount effective to kill the filarial worm.In another aspect, provided herein is a method of inhibiting growth ormolt of a filarial worm, comprising: contacting the filarial worm with aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, in an amount effective to inhibitgrowth or molt of the filarial worm. In another aspect, provided hereinis a method of inhibiting motility of a filarial worm, comprising:contacting the filarial worm with a Heterocyclic Compound, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, in an amount effective to inhibit motility of thefilarial worm. In certain embodiments, the worm is an egg. In certainembodiments, the egg is an unfertilized egg. In certain embodiments, theegg is fertilized egg. In certain embodiments, the worm is a larva. Incertain embodiments, the worm is in a larval or juvenile stage. Incertain embodiments, the worm is a larva in any one of four larvalstages (L1, L2, L3, L4). In certain embodiments, the worm is a larva ofstage L1 or microfilaria. In certain embodiments, microfilaria is alarva of stage L1. In certain embodiments, the worm is a larva of stageL2. In certain embodiments, the worm is a larva of stage L3. In certainembodiments, the worm is a larva of stage L4. In certain embodiments theworm is in sexually immature stage (stage L5). In certain embodiments,the worm is mature. In certain embodiments, the worm is fully mature. Incertain embodiments, the worm is in adult stage. In certain embodiments,the worm is in pre-parasitic stage. In certain embodiments, the worm isin parasitic stage. In certain embodiments, the worm is contacted with aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, inside a subject. In certainembodiments, the worm is contacted with a Heterocyclic Compound, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, outside a subject.

As discussed herein, compounds provided herein are useful for treatingand preventing certain diseases and disorders in humans and animals. Incertain embodiments, a Heterocyclic Compound, or a pharmaceuticallyacceptable salt, tautomer, isotopologue, or stereoisomer thereof, isused to treat a disease caused by helminthic infection. In certainembodiments, a Heterocyclic Compound, or a pharmaceutically acceptablesalt, tautomer, isotopologue, or stereoisomer thereof, is used to treata disease caused by parasitic worm infection, including, but not limitedto, heartworm disease, ascariasis, trichuriasis, schistosomiasis,haemonchosis, onchocerciasis, and lymphatic filariasis. In certainembodiments, treatment or prevention of such diseases and disorders canbe effected by administering a Heterocyclic Compound, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, either alone or in combination with another activeagent as part of a combination therapy. The term “combination” as in thephrase “in combination with another active agent” includesco-administration of a first agent and a second agent, which for examplemay be dissolved or intermixed in the same pharmaceutically acceptablecarrier, or administration of a first agent, followed by the secondagent, or administration of the second agent, followed by the firstagent. The present methods and compositions, therefore, include methodsof combination therapeutic treatment and combination pharmaceuticalcompositions. The term “combination therapy” refers to theadministration of two or more therapeutic substances, such as a compounddescribed herein and another drug (e.g., an antihelminthic agent such asivermectin, albendazole, flubendazole, diethylcarbamazine, oremodepside). The other drug(s) may be administered concomitant with,prior to, or following the administration of the macrolide antibiotic.

In one embodiment, provided is a method for the treatment or preventionof helminthic infections and diseases, the methods comprisingadministering to a subject an effective amount of a HeterocyclicCompound, or a pharmaceutically acceptable salt, tautomer, isotopologue,or stereoisomer thereof, in combination with one or more antihelminthicagent. In some such embodiments, the helminthic infection is a filarialworm infection. In one embodiment, the treatment of helminthicinfections comprises administration of an antihelminthic agent such asbenzimidazoles, for example, flubendazole, albendazole, mebendazole,thiabendazole, fenbendazole, or triclabendazole. In one embodiment, thetreatment of helminthic infections comprises administration of one ormore antihelminthic agents, for example, ivermectin, abamectin,diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole,niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside,monepantel, derquantel, oxfendazole, or pelletierine sulphate. In oneembodiment, the antihelminthic agent is invermectin, moxidectin orselamectin. In certain embodiments, a Heterocyclic Compound, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, is used to treat helminthic infections incombination with one or more antihelminthic agents. In some embodiments,the antihelminthic agent is a benzimidazole, for example, flubendazole,albendazole, mebendazole, thiabendazole, fenbendazole, ortriclabendazole. In some embodiments, the antihelminthic agent is one ormore of ivermectin, abamectin, diethylcarbamazine (DEC), suramin,pyrantel pamoate, levamisole, niclosamide, nitazoxanide, oxyclozanide,praziquantel, emodepside, monepantel, derquantel, oxfendazole, orpelletierine sulphate. In one embodiment, the antihelminthic agent isinvermectin, moxidectin or selamectin. In certain embodiments, aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, is used in a method of treatmentor prevention of filarial worm infections and diseases, the methodcomprising administering to a subject an effective amount of aHeterocyclic Compound, or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof in combination with one or moreantihelminthic agents. In some such embodiments, the antihelminthicagent is selected from flubendazole, albendazole, mebendazole,thiabendazole, fenbendazole, triclabendazole, ivermectin, abamectin,diethylcarbamazine (DEC), suramin, pyrantel pamoate, levamisole,niclosamide, nitazoxanide, oxyclozanide, praziquantel, emodepside,monepantel, derquantel, oxfendazole, or pelletierine sulphate. In oneembodiment, the antihelminthic agent is invermectin, moxidectin orselamectin. In one embodiment, the antihelminthic agent is a Wolbachiatargeting agent. In one embodiment, the Wolbachia targeting agent isdoxycycline.

Pharmaceutical Compositions and Routes of Administration

Provided herein are pharmaceutical compositions comprising an effectiveamount of a Heterocyclic Compound, as described herein, and apharmaceutically acceptable carrier, excipient or vehicle. TheHeterocyclic Compounds can be administered to a subject enterally (forexample, orally, rectally), topically, or parenterally (for example,intravenously, intramuscularly, subcutaneously), in the conventionalform of preparations, such as capsules, microcapsules, tablets,granules, powder, troches, pills, suppositories, injections,suspensions, syrups, patches, creams, lotions, ointments, gels, sprays,solutions and emulsions. Suitable formulations can be prepared bymethods commonly employed using conventional, organic or inorganicadditives, such as an excipient (e.g., sucrose, starch, mannitol,sorbitol, lactose, glucose, cellulose, talc, calcium phosphate orcalcium carbonate), a binder (e.g., cellulose, methylcellulose,hydroxymethylcellulose, polypropylpyrrolidone, polyvinylpyrrolidone,gelatin, gum arabic, polyethyleneglycol, sucrose or starch), adisintegrator (e.g., starch, carboxymethylcellulose,hydroxypropylstarch, low substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate or calcium citrate), a lubricant (e.g.,magnesium stearate, light anhydrous silicic acid, talc or sodium laurylsulfate), a flavoring agent (e.g., citric acid, menthol, glycine ororange powder), a preservative (e.g., sodium benzoate, sodium bisulfite,methylparaben or propylparaben), a stabilizer (e.g., citric acid, sodiumcitrate or acetic acid), a suspending agent (e.g., methylcellulose,polyvinyl pyrrolidone or aluminum stearate), a dispersing agent (e.g.,hydroxypropylmethylcellulose), a diluent (e.g., water), a cosolvent(e.g., propylene glocyl/glycofurol), a buffer, a copolymer (e.g.,poly(lactic-co-glycolic acid, i.e PLGA), and base wax (e.g., cocoabutter, white petrolatum or polyethylene glycol). The effective amountof the Heterocyclic Compound in the pharmaceutical composition may be ata level that will exercise the desired effect; for example, about 0.005mg/kg of a subject's body weight to about 20 mg/kg of a subject's bodyweight in unit dosage for both oral and parenteral administration.

The dose of a Heterocyclic Compound to be administered to a subject israther widely variable and can be subject to the judgment of ahealth-care practitioner. In general, the Heterocyclic Compound can beadministered one to four times a day in a dose of about 0.5 mg/kg of asubject's body weight to about 20 mg/kg of a subject's body weight in asubject, but the above dosage may be properly varied depending on theage, body weight and medical condition of the subject and the type ofadministration. In one embodiment, the dose is about 0.1 mg/kg of asubject's body weight to about 3 mg/kg of a subject's body weight, about0.5 mg/kg of a subject's body weight to about 2 mg/kg of a subject'sbody weight, about 1 mg/kg of a subject's body weight to about 2 mg/kgof a subject's body weight or about 1.5 mg/kg of a subject's body weightto about 2 mg/kg of a subject's body weight. In one embodiment, the doseis about 1 mg/kg of a subject's body weight to about 3 mg/kg of asubject's body weight. In one embodiment, the dose is about 0.5 mg/kg ofa subject's body weight to about 1 mg/kg of a subject's body weight. Inone embodiment, the dose is about 1 mg/kg of a subject's body weight toabout 2 mg/kg of a subject's body weight. In one embodiment, the dose isabout 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7,2.8, 2.9, 3.0 mg/kg of a subject's body weight. In one embodiment, onedose is given per day. In any given case, the amount of the HeterocyclicCompound administered will depend on such factors as the solubility ofthe active component, the formulation used and the route ofadministration. In one embodiment, application of a topicalconcentration provides intracellular exposures or concentrations ofabout 0.01-10 μM.

In another embodiment, provided herein are methods for the treatment orprevention of a disease or disorder comprising the administration ofabout 1 mg/day to about 1200 mg/day of a Heterocyclic Compound to asubject affected by helmintics infections. In another embodiment,provided herein are methods for the treatment or prevention of a diseaseor disorder comprising the administration of about 0.375 mg/day to about750 mg/day, about 0.75 mg/day to about 375 mg/day, about 3.75 mg/day toabout 75 mg/day, about 7.5 mg/day to about 55 mg/day or about 18 mg/dayto about 37 mg/day of a Heterocyclic Compound to a subject affected byhelmintics infections. In one embodiment, the methods for the treatmentof a disease or disorder comprise the administration of about 0.375mg/day to about 750 mg/day of a Heterocyclic Compound to a subjectaffected by helmintics infections. In one embodiment, the methods forthe treatment of a disease or disorder comprise the administration ofabout 0.75 mg/day to about 375 mg/day of a Heterocyclic Compound to asubject affected by helmintics infections. In one embodiment, themethods for the treatment of a disease or disorder comprise theadministration of about 3.75 mg/day to about 75 mg/day of a HeterocyclicCompound to a subject affected by helmintics infections. In oneembodiment, the methods for the treatment of a disease or disordercomprise the administration of about 7.5 mg/day to about 55 mg/day of aHeterocyclic Compound to a subject affected by helmintics infections. Inone embodiment, the methods for the treatment of a disease or disordercomprise the administration of about 18 mg/day to about 37 mg/day of aHeterocyclic Compound to a subject affected by helmintics infections.

In another embodiment, provided herein are unit dosage formulations thatcomprise between about 1 mg and 200 mg, about 35 mg and about 1400 mg,about 125 mg and about 1000 mg, about 250 mg and about 1000 mg, or about500 mg and about 1000 mg of a Heterocyclic Compound. In one embodiment,the unit dosage formulations comprises between about 1 mg and 200 mg ofa Heterocyclic Compound. In one embodiment, the unit dosage formulationscomprises between about 35 mg and about 1400 mg of a HeterocyclicCompound. In one embodiment, the unit dosage formulations comprisesbetween about 125 mg and about 1000 mg of a Heterocyclic Compound. Inone embodiment, the unit dosage formulations comprises between about 250mg and about 1000 mg of a Heterocyclic Compound. In one embodiment, theunit dosage formulations comprises between about 500 mg and about 1000mg of a Heterocyclic Compound.

In a particular embodiment, provided herein are unit dosage formulationscomprising about 100 mg or 400 mg of a Heterocyclic Compound.

In another embodiment, provided herein are unit dosage formulations thatcomprise 1 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 35 mg, 40 mg, 50 mg, 70mg, 100 mg, 125 mg, 130, mg, 140 mg, 175 mg, 200 mg, 250 mg, 280 mg, 350mg, 500 mg, 560 mg, 700 mg, 750 mg, 1000 mg or 1400 mg of a HeterocyclicCompound. In one embodiment, the unit dosage formulations comprise 1 mgof a Heterocyclic Compound. In one embodiment, the unit dosageformulations comprise 5 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 10 mg of aHeterocyclic Compound. In one embodiment, the unit dosage formulationscomprise 15 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 20 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 25 mg of aHeterocyclic Compound. In one embodiment, the unit dosage formulationscomprise 30 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 35 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 40 mg of aHeterocyclic Compound. In one embodiment, the unit dosage formulationscomprise 50 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 70 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 100 mg of aHeterocyclic Compound. In one embodiment, the unit dosage formulationscomprise 125 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 130 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 140 mg of aHeterocyclic Compound. In one embodiment the unit dosage formulationscomprise 175 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 200 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 250 mg of aHeterocyclic Compound. In one embodiment, the unit dosage formulationscomprise 280 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 350 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 500 mg of aHeterocyclic Compound. In one embodiment, the unit dosage formulationscomprise 560 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 700 mg of a Heterocyclic Compound. In oneembodiment, the unit dosage formulations comprise 750 mg of aHeterocyclic Compound. In one embodiment, the unit dosage formulationscomprise 1000 mg of a Heterocyclic Compound. In one embodiment, the unitdosage formulations comprise 1400 mg of a Heterocyclic Compound.

A Heterocyclic Compound can be administered once, twice, three, four ormore times daily. In a particular embodiment, doses of 600 mg or lessare administered as a once daily dose and doses of more than 600 mg areadministered twice daily in an amount equal to one half of the totaldaily dose.

A Heterocyclic Compound can be administered orally for reasons ofconvenience. In one embodiment, when administered orally, a HeterocyclicCompound is administered with a meal and water. In another embodiment,the Heterocyclic Compound is dispersed in water or juice (e.g., applejuice or orange juice) and administered orally as a suspension.

The Heterocyclic Compound can also be administered intradermally,intramuscularly, intraperitoneally, percutaneously, intravenously,subcutaneously, intranasally, epidurally, sublingually, intracerebrally,intravaginally, transdermally, rectally, mucosally, by inhalation, ortopically to the ears, nose, eyes, or skin, or by local ocular (i.e.,subconjunctival, intravitreal, retrobulbar, intracameral). The mode ofadministration is left to the discretion of the health-carepractitioner, and can depend in-part upon the site of the medicalcondition.

In one embodiment, provided herein are capsules containing aHeterocyclic Compound without an additional carrier, excipient orvehicle.

In another embodiment, provided herein are compositions comprising aneffective amount of a Heterocyclic Compound and a pharmaceuticallyacceptable carrier or vehicle, wherein a pharmaceutically acceptablecarrier or vehicle can comprise an excipient, diluent, or a mixturethereof. In one embodiment, the composition is a pharmaceuticalcomposition.

The compositions can be in the form of tablets, chewable tablets,capsules, solutions, parenteral solutions, troches, suppositories,suspensions, gels, intra-ruminal devices (e.g., for prolongedprophylaxis or controlled release), implants, topical pour-ons,transdermal delivery gels, spot-ons, implants (including devices, gels,liquids (e.g., PLGA), and the like. Compositions can be formulated tocontain a daily dose, or a convenient fraction of a daily dose, in adosage unit, which may be a single tablet or capsule or convenientvolume of a liquid. In one embodiment, the solutions are prepared fromwater-soluble salts, such as the hydrochloride salt. In general, all ofthe compositions are prepared according to known methods inpharmaceutical chemistry. Capsules can be prepared by mixing aHeterocyclic Compound with a suitable carrier or diluent and filling theproper amount of the mixture in capsules. The usual carriers anddiluents include, but are not limited to, inert powdered substances suchas starch of many different kinds, powdered cellulose, especiallycrystalline and microcrystalline cellulose, sugars such as fructose,mannitol and sucrose, grain flours and similar edible powders.

Tablets can be prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant might be necessary in a tablet formulation to prevent thetablet and punches from sticking in the dye. The lubricant can be chosenfrom such slippery solids as talc, magnesium and calcium stearate,stearic acid and hydrogenated vegetable oils. Tablet disintegrators aresubstances that swell when wetted to break up the tablet and release thecompound. They include starches, clays, celluloses, algins and gums.More particularly, corn and potato starches, methylcellulose, agar,bentonite, wood cellulose, powdered natural sponge, cation-exchangeresins, alginic acid, guar gum, citrus pulp and carboxymethyl cellulose,for example, can be used as well as sodium lauryl sulfate. Tablets canbe coated with sugar as a flavor and sealant, or with film-formingprotecting agents to modify the dissolution properties of the tablet.The compositions can also be formulated as chewable tablets, forexample, by using substances such as mannitol in the formulation.

When it is desired to administer a Heterocyclic Compound as asuppository, typical bases can be used. Cocoa butter is a traditionalsuppository base, which can be modified by addition of waxes to raiseits melting point slightly. Water-miscible suppository bases comprising,particularly, polyethylene glycols of various molecular weights are inwide use.

The effect of the Heterocyclic Compound can be delayed or prolonged byproper formulation. For example, a slowly soluble pellet of theHeterocyclic Compound can be prepared and incorporated in a tablet orcapsule, or as a slow-release implantable device. The technique alsoincludes making pellets of several different dissolution rates andfilling capsules with a mixture of the pellets. Tablets or capsules canbe coated with a film that resists dissolution for a predictable periodof time. Even the parenteral preparations can be made long-acting, bydissolving or suspending the Heterocyclic Compound in oily or emulsifiedvehicles, or adding amounts of PLGA, that allow it to disperse slowly inthe serum.

EXAMPLES

The following Examples are presented by way of illustration, notlimitation. Compounds are named using the automatic name generating toolprovided in Chemdraw Ultra 13.0 (Cambridgesoft), which generatessystematic names for chemical structures, with support for theCahn-Ingold-Prelog rules for stereochemistry. One skilled in the art canmodify the procedures set forth in the illustrative examples to arriveat the desired products.

Abbreviations used:

Ac₂O Acetic anhydride BINAP(2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl) nBuLi n-Butyl lithium DCMDichloromethane DIPEA Diisopropylethylamine DMF N,N-DimethylformamideDMSO Dimethylsulfoxide EDCIN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride ESIElectrospray ionization EtOAc Ethyl acetate EtOH Ethanol H₂O Water HATUO-(7-Azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HEPES (4-(2-Hydroxyethyl)-1-piperazineethanesulfonicacid) HPLC High performance liquid chromatography LCMS Liquidchromatography mass spectrometry m-CPBA meta-Chloroperoxybenzoic acidMeCN or ACN Acetonitrile MeOH Methanol MS Mass spectrometry MTBE Methyltertiary butyl ether NaH Sodium hydride NBS N-Bromosuccinimide NH₄ClAmmonium chloride NMR Nuclear magnetic resonance Pd/C Palladium (0) oncarbon Pd(PPh₃)₂Cl₂ Bis(triphenylphosphine)palladium (II) dichloridePd(PPh₃)₄ Tetrakis(triphenylphosphine)palladium (0) Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium (0) TEA Triethylamine THFTetrahydrofuran TLC Thin layer chromatography UPLC Ultra PerformanceLiquid Chromatography UHPLC Ultra High Performance Liquid ChromatographyXantphos 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene

Compound Synthesis Example 1:3-(4-Isopropylpyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

4-(Prop-1-en-2-yl)picolinonitrile

To a mixture of 4-bromopicolinonitrile (12.0 g, 65.5 mmol) in DMSO (100mL) was added potassium carbonate (19.9 g, 144 mmol), Pd(dppf)C₁₂ (4.80g, 6.56 mmol) and potassium trifluoro(prop-1-en-2-yl)borate (10.6 g,72.1 mmol). The mixture was degassed with nitrogen for 3 times. Themixture was stirred at 100° C. for 8 h. The mixture was poured into H₂Oand extracted with EtOAc. The organic layers were concentrated to givethe crude product, which was purified by silica gel chromatography togive 4-isopropenylpyridine-2-carbonitrile (5.00 g, 34.6 mmol, 52.89%yield).

4-(Prop-1-en-2-yl)picolinimidamide

To a mixture of 4-(prop-1-en-2-yl)picolinonitrile (3.30 g, 22.8 mmol) inMeOH (30 mL) was added sodium methoxide (618 mg, 11.4 mmol). Thereaction mixture was then stirred at 25° C. for 10 h. NH₄Cl (2.08 g,38.9 mmol) was added to the mixture and the mixture was then stirred at75° C. for another 3 h. The mixture was concentrated to remove MeOH andthe residue was diluted with EtOH (50 mL). The mixture was warmed to 70°C. and stirred at this temperature for 0.5 h. Then the mixture wasfiltered and the filtrate was concentrated to remove EtOH to give thecrude product, which was diluted with ACN (150 mL) and H₂O (30 mL).OH-type resin (10 g) was added to the mixture and filtered, and thefiltrate was concentrated and lyophilized to give4-(prop-1-en-2-yl)picolinimidamide (5.40 g, crude).

4-Isopropylpicolinimidamide

To a mixture of 4-isopropenylpyridine-2-carboxamidine (5.30 g, 32.8mmol) in MeOH (60 mL) was added palladium/C (0.5 g, 32.8 mmol, 10%purity). The suspension was degassed under vacuum and purged withhydrogen several times. The mixture was stirred under hydrogen (15 psi)at 20° C. for 2 h. The solution was filtered and the filtrate wasconcentrated in vacuum to give crude product 4-isopropylpicolinimidamide(5 g, crude).

4-Isopropyl-N-((4-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide

To a mixture of 4-isopropylpicolinimidamide (0.70 g, 4.29 mmol) and2-isothiocyanato-4-(trifluoromethyl)pyridine (875 mg, 4.29 mmol) inacetone (10 mL) and DCM (10 mL) was added TEA (867 mg, 8.58 mmol) undernitrogen. The reaction was stirred at 20° C. for 1 h. The mixture waspoured into H₂O (40 mL) and extracted with DCM. The combined organicphases were washed with H₂O, dried with anhydrous sodium sulfate,filtered, and concentrated in vacuum to give4-isopropyl-N-((4-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide (1.58 g, crude).

3-(4-Isopropylpyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of4-isopropyl-N-((4-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide (1.58 g, 4.30 mmol) in EtOH (15 mL) was added iodine(218 mg, 860.12 μmol) and hydrogen peroxide (975 mg, 8.60 mmol, 30%purity). The mixture was stirred at 20° C. for 0.5 h. The mixture waspoured into saturated sodium sulfite (30 mL) and extracted with EtOAc.The combined organic phases were washed with H₂O, dried with anhydroussodium sulfate, filtered, and concentrated in vacuum. The product wasisolated and purified via standard methods to give3-(4-isopropylpyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(267.09 mg, 720 μmol, 16.7% yield, 97.72% purity). LCMS (ESI): m/z 366.1[M+1]⁺.

Example 2:3-(4-Cyclopropylpyridin-2-yl)-N-(3-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

4-Cyclopropylpicolinonitrile

To a mixture of 4-bromopicolinonitrile (11.18 g, 61.0 mmol),cyclopropylboronic acid (5.25 g, 61.0 mmol) and potassium carbonate(16.89 g, 122.0 mmol) in dioxane (400 mL) was added Pd(dppf)Cl₂ (2.24 g,3.05 mmol) under nitrogen. The mixture was stirred at 100° C. for 5 h.The mixture was concentrated to remove dioxane and the residue wasdiluted with H₂O. The aqueous phase was extracted with EtOAc. Thecombined organic phases were dried with anhydrous sodium sulfate,filtered, and concentrated to give crude product which was purified bysilica gel chromatography to give 4-cyclopropylpicolinonitrile (8.3 g,50.0 mmol, 81.8% yield, 86.9% purity).

4-Cyclopropylpicolinimidamide

To a mixture of 4-cyclopropylpicolinonitrile (5.00 g, 34.6 mmol) in MeOH(50 mL) was added sodium methoxide (936 mg, 17.3 mmol). The reactionmixture was then stirred at 25° C. for 15 h. NH₄Cl (3.15 g, 58.9 mmol)was added to the mixture and the mixture was then stirred at 75° C. foranother 3 h. The mixture was concentrated to remove MeOH and thendiluted with EtOH. The mixture was warmed to 70° C. and stirred for 0.5h. Then the mixture was filtered and the filtrate was concentrated toremove EtOH to afford the crude product. The crude product was thendiluted with ACN and H₂O. OH-type resin (10 g) was added to the mixtureand the mixture was stirred at 25° C. for 0.5 h. Then the mixture wasfiltered and the filtrate was concentrated and lyophilized to give4-cyclopropylpicolinimidamide (5.1 g, crude).

2-Isothiocyanato-3-(trifluoromethyl)pyridine

To a mixture of thiophosgene (3.55 g, 30.8 mmol) in DCM (50 mL) wasadded a solution of 3-(trifluoromethyl)pyridin-2-amine (5 g, 30.8 mmol)in DCM (150 mL) under nitrogen. The mixture was stirred at 0° C. for 1h. The mixture was poured into saturated sodium bicarbonate andextracted with DCM. The combined organic phases were washed with H₂O,dried with anhydrous sodium sulfate, filtered, and concentrated invacuum. The residue was purified by silica gel chromatography to give2-isothiocyanato-3-(trifluoromethyl)pyridine (3.50 g, 17.1 mmol, 55.5%yield).

4-Cyclopropyl-N-((3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide

To a mixture of 4-cyclopropylpicolinimidamide (1.00 g, 6.20 mmol) and2-isothiocyanato-3-(trifluoromethyl)pyridine (1.27 g, 6.20 mmol) inacetone (2 mL) and DCM (2 mL) was added TEA (1.26 g, 12.4 mmol) undernitrogen. The reaction was stirred at 20° C. for 1 h. The mixture waspoured into H₂O and extracted with DCM. The combined organic phases werewashed with H₂O, dried with anhydrous sodium sulfate, filtered, andconcentrated in vacuum to give4-cyclopropyl-N-((3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide (1 g, crude).

3-(4-Cyclopropylpyridin-2-yl)-N-(3-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of4-cyclopropyl-N-((3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide(1.20 g, 3.28 mmol) in EtOH (15 mL) was added iodine (166 mg, 656 μmol)and hydrogen peroxide (223 mg, 6.57 mmol). The mixture was stirred at20° C. for 0.5 h. The mixture was poured into saturated sodium sulfiteand extracted with EtOAc. The product was isolated and purified viastandard methods to give3-(4-cyclopropylpyridin-2-yl)-N-(3-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(397.62 mg, 1.08 mmol, 32.9% yield, 99% purity). LCMS (ESI): m/z 364.0[M+1]⁺.

Example 3:N-(3-Methylpyridin-2-yl)-3-(5-(methylsulfonyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

5-(Methylthio)picolinonitrile

To a mixture of 5-fluoropicolinonitrile (10 g, 81.9 mmol) in DMF (150mL) was added sodium methanethiolate (6.89 g, 98.3 mmol) at 0° C. Themixture was stirred at 0° C. for 0.5 h and then warmed to 20° C. Themixture was stirred at 20° C. for 2 h. The mixture was poured intosaturated NH₄Cl (2 L) and then extracted with EtOAc. The organic layerswere concentrated to give 5-(methylthio)-picolinonitrile (8.5 g, 51.0mmol, 62.27% yield, 90.12% purity) and used without furtherpurification.

5-(Methylthio)picolinimidamide

To a mixture of 5-(methylthio)picolinonitrile (4.00 g, 26.6 mmol) inMeOH (50 mL) was added sodium methoxide (475.0 mg, 8.80 mmol) and themixture was stirred at 20° C. for 10 h. NH₄Cl (3.13 g, 58.6 mmol) wasadded. The mixture was heated to 70° C. and stirred for 10 h. Themixture concentrated under reduce pressure to remove MeOH. The residuewas dissolved in EtOH (100 mL) and the mixture was stirred at 70° C. for1 h. The mixture is filtered and the filtrate was concentrated. Theresidue was then triturated by DCM (100 mL). The product was collectedas a solid by filtration. The solid was dissolved in ACN (100 mL) andH₂O (20 mL). Amberlyst A 26 (3.50 g) was added and the mixture wasstirred at 20° C. for 15 min. The mixture was filtered and the filtratewas concentrated and then diluted with toluene. The mixture wasconcentrated to give 5-methylsulfanylpyridine-2-carboxamidine (3.5 g,20.9 mmol, 78.6% yield).

N-(3-Methylpyridin-2-yl)-3-(5-(methylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of 5-(methylthio)picolinimidamide (2.00 g, 11.9 mmol) inDCM (50 mL), acetone (50 mL) and DMF (50 mL) were added TEA (6.05 g,59.8 mmol) and 2-isothiocyanato-3-methylpyridine (2.69 g, 17.9 mmol).The mixture was stirred at 20° C. for 10 h. The mixture wasconcentrated. The residue was purified by prep-HPLC to giveN-(3-methylpyridin-2-yl)-3-(5-(methylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(450 mg, 718.0 μmol, 6.00% yield).

N-(3-Methylpyridin-2-yl)-3-(5-(methylsulfonyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture ofN-(3-methylpyridin-2-yl)-3-(5-(methylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(230 mg, 729.0 μmol) in DMF (10 mL) was added 2-chlorobenzoperoxoic acid(370.0 mg, 1.8 mmol, 85% purity). The mixture was stirred at 0° C. for 1h. The reaction was quenched with saturated sodium sulfite (6 mL) thenpoured into H₂O (100 mL). The product was isolated and purified viastandard methods to giveN-(3-methylpyridin-2-yl)-3-(5-(methylsulfonyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(208.3 mg, 302.2 μmol, 41.12% yield). LCMS (ESI): m/z 348.1 [M+1]⁺.

Example 4:N-(3-Cyclopropylpyridin-2-yl)-3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-amine

3-Cyclopropylpyridin-2-amine

To a mixture of 3-bromopyridin-2-amine (5 g, 28.9 mmol),cyclopropylboronic acid (3.23 g, 37.5 mmol) and potassium carbonate(13.9 g, 101 mmol) in dioxane (30 mL) and H₂O (3 mL) was addedPd(dppf)Cl₂(4.23 g, 5.78 mmol) under nitrogen. The reaction was stirredat 100° C. under nitrogen for 2 h. The mixture was poured into H₂O andextracted with EtOAc. The combined organic phases were washed withbrine, dried with anhydrous sodium sulfate, filtered, and concentratedin vacuum to give crude product which was purified by silica gelchromatography to give 3-cyclopropylpyridin-2-amine (2.5 g, 18.0 mmol,62.6% yield, 97.1% purity).

3-Cyclopropyl-2-isothiocyanatopyridine

To a mixture of thiophosgene (3.21 g, 27.9 mmol) in DCM (10 mL) wasadded 3-cyclopropylpyridin-2-amine (2.5 g, 18.6 mmol) at 0° C. Then themixture was stirred at 20° C. for 0.5 h. The reaction mixture was washedby saturated sodium bicarbonate, the organic phase was dried byanhydrous sodium sulfate, and then concentrated under reduced pressureto give red oil. The red oil was purified by silica gel chromatographyto give 3-cyclopropyl-2-isothiocyanatopyridine (1.3 g, 6.79 mmol, 36.4%yield, 92% purity).

N-((3-Cyclopropylpyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide

To a mixture of 3-cyclopropyl-2-isothiocyanatopyridine (1.2 g, 6.81mmol) and TEA (1.38 g, 13.6 mmol) in DCM (10 mL) and acetone (10 mL) wasadded 5-isopropoxypyridine-2-carboxamidine (1.22 g, 6.81 mmol) undernitrogen. The reaction was stirred at 20° C. for 2 h. The solution waspoured into H₂O and the aqueous phase was extracted with DCM. Thecombined organic phases were washed with H₂O, dried with anhydroussodium sulfate, filtered, and concentrated in vacuum to giveN-((3-cyclopropylpyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide(1.8 g, 3.04 mmol, 44.6% yield, 60% purity).

N-(3-Cyclopropylpyridin-2-yl)-3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture ofN-((3-cyclopropylpyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide(1.8 g, 3.04 mmol) in EtOH (10 mL) was added a solution of iodine (154mg, 607 μmol) in EtOH (2 mL) and hydrogen peroxide (688 mg, 6.08 mmol30% purity) under nitrogen. The mixture was stirred at 20° C. for 2 h.The mixture was poured into saturated sodium sulphite (50 ml) andextracted with DCM. The product was isolated and purified via standardmethods to giveN-(3-cyclopropylpyridin-2-yl)-3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-amine(153.37 mg, 385 μmol, 13.7% yield, 97.9% purity, HCl). LCMS (ESI): m/z354.1 [M+1]⁺.

Example 5:N²-(3-(5-Cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine

N,N-Dimethyl-2-nitropyridin-3-amine

To a mixture of 3-fluoro-2-nitropyridine (30 g, 211.0 mmol) andpotassium carbonate (116.7 g, 8445 mmol) in ACN (500 mL) was addeddimethylamine hydrochloride (25.8 g, 317.0 mmol). The reaction mixturewas stirred at 20° C. for 2 h. The mixture was concentrated to removeACN and then diluted with H₂O and EtOAc. The aqueous phase was extractedwith EtOAc. The combined organic phases were dried with anhydrous sodiumsulfate, filtered, and concentrated to giveN,N-dimethyl-2-nitropyridin-3-amine (34 g, 201.0 mmol, 95.18% yield,98.8% purity).

N³,N³-Dimethylpyridine-2,3-diamine

To a mixture of N,N-dimethyl-2-nitropyridin-3-amine (30 g, 180 mmol) inMeOH (200 mL) and glycol dimethyl ether (200 mL) was added Pd/C (3 g,180 mmol, 10% purity) under N₂. The reaction was degassed under N₂ andpurged with H₂ 3 times. The reaction mixture was then stirred at 30° C.under H₂ (50 psi) for 5 h. The solution was filtered, concentrated andpurified by silica gel chromatography to give N³,N³-dimethylpyridine-2,3-diamine (24 g, 169.5 mmol, 94.46% yield, 96.9%purity).

2-Isothiocyanato-N,N-dimethylpyridin-3-amine

To mixture of thiophosgene (7.54 g, 65.6 mmol) in DCM (50 mL) was addedN³,N³-dimethylpyridine-2,3-diamine (3 g, 21.9 mmol) at 0° C. under N₂.The mixture was stirred at 20° C. for 3 h. The mixture was poured intosaturated sodium bicarbonate and extracted with DCM. The combinedorganic phases were washed with saturated sodium bicarbonate, dried withanhydrous sodium sulfate, filtered and concentrated in vacuum to give2-isothiocyanato-N,N-dimethylpyridin-3-amine (2.3 g, crude).

N²-(3-(5-Cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine

To a mixture of 2-isothiocyanato-N,N-dimethylpyridin-3-amine (1.01 g,5.64 mmol and DIPEA (1.46 g, 11.29 mmol) in DCM (20 mL) and acetone (20mL) was added 5-cyclopropoxypicolinimidamide (1 g, 5.64 mmol) under N₂.The mixture was stirred at 20° C. for 10 h. The mixture was poured intoH₂O and extracted with DCM. The product was isolated and purified viastandard methods to giveN²-[3-[5-(cyclopropoxy)-2-pyridyl]-1,2,4-thiadiazol-5-yl]-N³,N³-dimethyl-pyridine-2,3-diamine;HCl salt (277 mg, 0.709 mmol, 12.56% yield, 100% purity).

Example 6:3-(5-(Cyclopropylmethoxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

5-(Cyclopropylmethoxy)picolinonitrile

To a mixture of cyclopropylmethanol (6.26 g, 86.8 mmol) in DMF (300 mL)was added NaH (3.60 g, 90.1 mmol, 60% purity) at 0° C. and stirred 1 h.5-fluoropicolinonitrile (10 g, 81.9 mmol) was added at 0° C. and stirredfor 1 h. Then the mixture was stirred at 20° C. for 1 h. The mixture waspoured into saturated NH₄Cl. The aqueous phase was extracted with EtOAc.The combined organic layers were concentrated to give5-(cyclopropylmethoxy)picolinonitrile (10.20 g, 55.6 mmol, 67.91% yield,94.99% purity) which was used directly to next step.

5-(Cyclopropylmethoxy)picolinimidamide

To a mixture of 5-(cyclopropylmethoxy)picolinonitrile (9.00 g, 51.7mmol) in MeOH (100 mL) was added sodium methoxide (976.90 mg, 18.1mmol). The mixture was heated to 70° C. and stirred at 20° C. for 10 h.NH₄Cl (6.36 g, 118.8 mmol) was added and the mixture was stirred at 70°C. for 10 h. The solvent was concentrated under reduced pressure toremove MeOH. The residue was dissolved in EtOH (100 mL) and heated to70° C. for 1 h. The mixture was filtered at 70° C. The filtrate wasconcentrated. The residue was then triturated with DCM and thenfiltered. The solid was dissolved in ACN and H₂O. Amberlyst A 26 (4.00g) was added and the mixture was stirred at 20° C. for 15 min. Themixture was filtered and the filtrate was concentrated and then toluene(50 mL) was added. The mixture was concentrated to give5-(cyclopropylmethoxy)picolinimidamide (3.61 g, 18.9 mmol, 36.54% yield,100% purity).

3-(5-(Cyclopropylmethoxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of 5-(cyclopropylmethoxy)picolinimidamide (3.50 g, 18.3mmol) and TEA (5.56 g, 54.9 mmol) in DCM (80 mL) and acetone (80 mL) wasadded a solution of 2-isothiocyanato-3-methylpyridine (4.12 g, 27.5mmol) in DCM (50 mL). The mixture was stirred at 20° C. for 10 h. Theproduct was isolated and purified via standard methods to give3-(5-(cyclopropylmethoxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine;HCl salt (214 mg, 556 mmol, 3.0% yield, 97.8% purity). LCMS (ESI): m/z340.1 [M+1]⁺.

Example7:3-(5-((2-Cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

5-((2-Cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)picolinonitrile

To a mixture of 5-(2-azaspiro[3.3]heptan-6-yloxy)picolinonitrile (1.57g, 7.29 mmol) in MeOH (20 mL) and acetic acid (10 mL) was added(1-ethoxycyclopropoxy)trimethylsilane (6.36 g, 36.5 mmol). The reactionmixture was stirred at 20° C. for 30 min. Then sodium cyanoborohydride(1.38 g, 21.9 mmol) was added to the mixture and the mixture was thenstirred at 80° C. for another 2 h. The mixture was concentrated undervacuum to give the residue. The residue was diluted with H₂O and the pHwas adjusted to 7 with ammonium hydroxide (25%). The mixture waspurified by C+ reverse column to give5-((2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)picolinonitrile (850mg, 3.11 mmol, 42.63% yield, 93.4% purity).

5-((2-Cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)picolinimidamide

To a mixture of5-((2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)picolinonitrile (400mg, 1.57 mmol) in MeOH (4 mL) was added sodium methoxide (42.3 mg, 783.0μmol) and the reaction mixture was then stirred at 25° C. for 15 h.NH₄Cl (126.0 mg, 2.35 mmol) was added to the mixture and the mixture wasthen stirred at 75° C. for another 12 h. The mixture was concentrated toremove MeOH and then diluted with EtOH (10 mL). The mixture was warmedto 70° C. and stirred at this temperature for 0.5 h. Then the mixturewas filtered and the filtrate was concentrated to give 520 mg crudeproduct (HCl salt), which was then diluted with ACN and H₂O. OH-typeresin (CAS: 39339-85-0, 1 g) was added to the mixture. The mixture wasfiltered and the filtrate was then lyophilized to give5-((2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)picolinimidamide (350mg, crude).

5-((2-Cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)-N-((3-methylpyridin-2-yl)carbamothioyl)picolinimidamide

To a mixture of5-((2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)picolinimidamide (350mg, 1.29 mmol) and TEA (260.0 mg, 2.57 mmol) in DCM (5 mL) was added asolution of 2-isothiocyanato-3-methyl-pyridine (193.0 mg, 1.29 mmol) inDCM (1 mL). The mixture was then stirred at 25° C. for 2 h. The mixturewas quenched with saturated sodium sulfite and then extracted withEtOAc. The combined organic phases were dried with anhydrous sodiumsulfate, filtered and concentrated to give5-((2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)-N-((3-methylpyridin-2-yl)carbamothioyl)picolinimidamide(660 mg, crude) which was used in the next step directly.

3-(5-((2-Cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of5-((2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy)-N-((3-methyl-pyridin-2-yl)carbamothioyl)picolinimidamide(660 mg, 1.56 mmol) in EtOH (10 mL) was added iodine (79.3 mg, 312.0μmol) and hydrogen peroxide (354.0 mg, 3.12 mmol, 30% purity). Thereaction mixture was then stirred at 25° C. for 1.5 h. The product wasisolated and purified via standard methods to give3-[5-[(2-cyclopropyl-2-azaspiro[3.3]heptan-6-yl)oxy]-2-pyridyl]-N-(3-methyl-2-pyridyl)-1,2,4-thiadiazol-5-amine(83.45 mg, 0.179 mmol, 11.45% yield, 100% purity). LCMS (ESI): m/z 421.2[M+1]⁺.

Example 8:3-(5-((1-Cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)pyridin-2-yl)-N-(3-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

Tert-Butyl4-((6-cyanopyridin-3-yl)oxy)-3,3-difluoropiperidine-1-carboxylate

To a mixture of NaH (786 mg, 19.7 mmol, 60% purity) in DMF (80 mL) wasadded tert-butyl 3,3-difluoro-4-hydroxypiperidine-1-carboxylate (3.89 g,16.4 mmol) at 0° C. and the mixture was warmed up to 15° C. stirring for0.5 h. Then the mixture was re-cooled to 0° C. and5-fluoropicolinonitrile (2.00 g, 16.4 mmol) was added in portions. Theresulting mixture was stirred at 0° C. for 0.5 h. The mixture was pouredinto saturated aqueous NH₄Cl (150 mL) and extracted with EtOAc. Theorganic phase was washed with H₂O and brine, dried over sodium sulfate,and filtered. The filtrate was concentrated under vacuum to givetert-butyl4-((6-cyanopyridin-3-yl)oxy)-3,3-difluoropiperidine-1-carboxylate (5.50g, crude) which was used directly without purification.

5-((3,3-Difluoropiperidin-4-yl)oxy)picolinonitrile

To a mixture of tert-butyl4-((6-cyanopyridin-3-yl)oxy)-3,3-difluoropiperidine-1-carboxylate (5.50g, 16.2 mmol) in DCM (50 mL) was added trifluoroacetic acid (15.4 g, 135mmol, 10 mL) dropwise at 0° C. and the mixture was stirred at 15° C. for2 h. The mixture was concentrated under vacuum to give5-((3,3-difluoropiperidin-4-yl)oxy)picolinonitrile (3.88 g, crude) whichwas neutralized with TEA in MeOH (40 mL) to pH=˜8 and used directly inthe next step without purification.

5-((1-Cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)picolinonitrile

To a mixture of 5-((3,3-difluoropiperidin-4-yl)oxy)picolinonitrile (3.88g, 16.2 mmol) in MeOH (40 mL) and acetic acid (20 mL) was added(1-ethoxycyclopropoxy)trimethylsilane (14.1 g, 81.1 mmol, 16.3 mL) at15° C. and the mixture was stirred at 15° C. for 0.5 h. Sodiumcyanoborohydride (3.06 g, 48.7 mmol) was added to the mixture at 15° C.and the resulting mixture was stirred at 80° C. for 2 h. The mixture wasconcentrated under vacuum to give the residue. The residue was dilutedwith saturated sodium carbonate under stirring and the resulting mixturewas extracted with EtOAc. The organic phase was washed with brine, driedover sodium sulfate, and filtered. The filtrate was concentrated undervacuum to give the crude product. The crude product was purified bysilica gel column chromatography (9%-25% EtOAc in petroleum ether) togive 5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)picolinonitrile(4.50 g, 12.9 mmol, 79.7% yield, 80.2% purity).

5-((1-Cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)picolinimidamide

To a solution of5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)picolinonitrile (1.50g, 4.31 mmol) in MeOH (30 mL) was added sodium methoxide (116 mg, 2.15mmol) at 15° C. and the mixture was stirred at 15° C. for 14 h. NH₄Cl(461 mg, 8.61 mmol) was added to the reaction mixture at 15° C. Themixture was stirred at 70° C. for another 2 h. The mixture wasconcentrated under vacuum to give a residue. The residue was dilutedwith EtOH (60 mL) and the mixture was stirred at 25° C. for 0.5 h. Themixture was filtered and the filtrate was concentrated under vacuum togive a solid which was triturated with EtOAc (50 mL) at 15° C. for 0.5h. The resulting mixture was filtered and the solid was collected, driedunder vacuum to give5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)picolinimidamide (1.28g, crude) as hydrochloride salt. The hydrochloride salt was dissolved inH₂O (60 mL), Amberlyst A 26 was added under stirring in portions untilthe pH of the solution was adjusted to 8 and stirred for 2 h at 15° C.The mixture was filtered and washed with H₂O (20 mL), and the filtratewas lyophilized for three days to give5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)picolinimidamide (0.960g, 1.65 mmol, 38.3% yield, 50.9% purity).

5-((1-Cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)-N-((3-isopropylpyridin-2-yl)carbamothioyl)picolinimidamide

To the mixture of5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)picolinimidamide (0.480g, 825 μmol) and TEA (167 mg, 1.65 mmol) in DCM (10 mL) and acetone (10mL) was added 3-isopropyl-2-isothiocyanatopyridine (273 mg, 1.24 mmol)at 15° C. under nitrogen atmosphere and the mixture was stirred at 15°C. for 2 h. The mixture was diluted with DCM and washed with H₂O. Theorganic phase was concentrated under vacuum to give5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)-N-((3-isopropylpyridin-2-yl)carbamo-thioyl)picolinimidamide(0.740 g, crude), which was used in the next step without purification.

3-(5-((1-Cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)pyridin-2-yl)-N-(3-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)-N-((3-isopropylpyridin-2-yl)carbamothioyl)picolinimidamide(0.730 g, 1.54 mmol) in EtOH (20 mL) was added hydrogen peroxide (349mg, 3.08 mmol, 30% purity) and a solution of iodine (78.1 mg, 308 μmol)in EtOH (2 mL). The mixture was stirred at 15° C. for 2 h. The productwas isolated and purified via standard methods to give3-(5-((1-cyclopropyl-3,3-difluoropiperidin-4-yl)oxy)pyridin-2-yl)-N-(3-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-amine(206.99 mg, 0.438 mmol, 28.5% yield, 100% purity). LCMS (ESI): m/z 473.3[M+1].

Example 9:N-(5-Cyclopentylpyridin-2-yl)-3-(5-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-amine

5-(Cyclopent-1-en-1-yl)-2-nitropyridine

To a mixture of 5-bromo-2-nitro-pyridine (2.5 g, 12.32 mmol),2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 g,15.39 mmol), sodium carbonate (2.61 g, 24.6 mmol) in dioxane (30 mL) andH2O (1.00 mL) was added tetrakis (triphenylphosphine) palladium (427.1mg, 0.369 mmol). The mixture was degassed and refilled with N₂. Themixture was stirred at 80° C. for 6 h. To the mixture was added anotherbath of 2-(cyclopenten-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(956.1 mg, 4.93 mmol) and tetrakis (triphenylphosphine) palladium (142.4mg, 0.123 mmol). The mixture was degassed and refilled with N₂ andstirred at 80° C. for an additional 3 h. Dichloro(1,1′-bis(diphenylphosphanyl)ferrocene) palladium(II) (180.29 mg, 0.246mmol) was added, the mixture was degassed and refilled with N₂ andstirred at 90° C. for an additional 6 h. The mixture was diluted withEtOAc and filtered. The filtrate was concentrated and the residuepurified by silica gel chromatography to give5-(cyclopenten-1-yl)-2-nitro-pyridine (1.60 g, 8.41 mmol, 68% yield).

5-Cyclopentylpyridin-2-amine

To a mixture of 5-(cyclopenten-1-yl)-2-nitro-pyridine (1.6 g, 8.41 mmol)in 2,2,2-trifluoroethanol (20 mL) was added Pd/C (2.0 g). The mixturewas degassed and refilled with H₂ (15 psi) and stirred at 30° C. for 2h. The mixture was stirred at 40° C. for 1 h. Then diluted with EtOAc,filtered and the filtrate concentrated. The residue was purified bysilica gel chromatography to give 5-cyclopentylpyridin-2-amine (900 mg,5.55 mmol, 66% yield).

5-Cyclopentyl-2-isothiocyanatopyridine

To a mixture of di(imidazol-1-yl)methanethione (549 mg, 3.08 mmol) inDMF (10 mL) was added a solution of 5-cyclopentylpyridin-2-amine (500mg, 3.08 mmol) in DMF (10 mL). The mixture was stirred at 10° C. for 1h. 5-Cyclopentyl-2-isothiocyanato-pyridine (629 mg, crude) in DMF (20mL) was used in the next step directly.

N-((5-Cyclopentylpyridin-2-yl)carbamothioyl)-5-methoxypicolinimidamide

To a mixture of 5-cyclopentyl-2-isothiocyanato-pyridine (629 mg, 3.1mmol) in DMF (20 mL) was added 5-methoxypyridine-2-carboxamidine (512mg, 3.4 mmol) and DIPEA (2 g, 15.4 mmol, 2.7 mL). The mixture wasstirred at 30° C. for 4 h. The mixture was diluted with H₂O. Theresultant mixture was extracted with EtOAc and the combined organiclayers were washed with saturated brine, dried over anhydrous sodiumsulfate, filtered, and concentrated to give1-(5-cyclopentyl-2-pyridyl)-3-(5-methoxypyridine-2-carboximidoyl)thiourea(1.1 g, crude), which was used in the next step directly.

N-(5-Cyclopentylpyridin-2-yl)-3-(5-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution of1-(5-cyclopentyl-2-pyridyl)-3-(5-methoxypyridine-2-carboximidoyl)thiourea(1.1 g, 3.1 mmol) in EtOH (20 mL) were added hydrogen peroxide (702 mg,6.2 mmol, 0.6 mL, 30% purity) and a solution of iodine (157 mg, 0.619mmol) in EtOH (5 mL). The mixture was stirred at 15° C. for 1 h. Theproduct was isolated and purified via standard methods to giveN-(5-cyclopentyl-2-pyridyl)-3-(5-methoxy-2-pyridyl)-1,2,4-thiadiazol-5-amine(576.40 mg, 1.61 mmol, 52% yield, 99% purity). LCMS (ESI): m/z 354.1[M+1]⁺.

Example10:3-(4-Isopropylpyridin-2-yl)-N-(3-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

4-(Prop-1-en-2-yl)picolinonitrile

To a mixture of 4-bromopicolinonitrile (2.00 g, 10.9 mmol) and potassiumtrifluoro(prop-1-en-2-yl)borate (3.23 g, 21.9 mmol) in 1,4-dioxane (20mL) and H₂O (2 mL) was added potassium carbonate (943 mg, 6.82 mmol) anddichloro(1,1′-bis(diphenylphosphanyl)ferrocene)palladium(II) chloroformcomplex (800 mg, 1.09 mmol) under nitrogen. The mixture was stirred at80° C. for 4 h. The mixture was poured into H₂O (100 mL). The aqueousphase was extracted with EtOAc. The combined organic phases were washedwith brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography to give 4-(prop-1-en-2-yl)picolinonitrile (1.44 g, 9.99mmol, 91.3% yield).

4-(Prop-1-en-2-yl)picolinimidamide Hydrochloride

To a mixture of 4-(prop-1-en-2-yl)picolinonitrile (1.65 g, 11.4 mmol) inMeOH (15 mL) was added sodium methanolate (185 mg, 3.43 mmol). Themixture was stirred at 30° C. for 16 h under nitrogen. NH₄Cl (796 mg,14.9 mmol) was added into the above mixture. The mixture was stirred at70° C. for 3 h. The mixture was concentrated in vacuo and the residuewas diluted with EtOH (80 mL). The mixture was refluxed at 80° C. for 15min. The mixture was filtered and the filter cake was triturated withDCM (30 mL), then dried in vacuo to give4-(prop-1-en-2-yl)picolinimidamide hydrochloride (1.70 g, 8.60 mmol, 75%yield).

4-Isopropylpicolinimidamide Hydrochloride

To a solution of 4-(prop-1-en-2-yl)picolinimidamide hydrochloride (1.60g, 8.09 mmol) in 2,2,2-trifluoroethanol (80 mL) was added Pd/C (480 mg).The mixture was stirred at 20° C. for 2.5 h under hydrogen balloon (15psi). The mixture was filtered through celite and the filtrateconcentrated in vacuo to give 4-isopropylpicolinimidamide hydrochloride(1.60 g, 8.01 mmol, 99.1% yield).

4-Isopropylpicolinimidamide

To a solution of 4-isopropylpicolinimidamide hydrochloride (1.80 g, 9.01mmol) in ACN (75 mL) and H₂O (15 mL) was added Amberlyst A 26. The pH ofthe mixture was adjusted to about 10-11. The mixture was stirred at 20°C. for 4 h. The reaction mixture was filtered and the filtrate wasconcentrated in vacuo followed by lyophilization to give4-isopropylpicolinimidamide (1.40 g, 8.49 mmol, 94% yield, 99% purity).

4-Isopropyl-N-((3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide

To a solution of 4-isopropylpyridine-2-carboxamidine (500 mg, 3.03 mmol)in DCM (5 mL) and acetone (5 mL) were added TEA (3.07 g, 30.30 mmol) and2-isothiocyanato-3-(trifluoromethyl)pyridine (635 mg, 3.03 mmol). Themixture was stirred at 15° C. for 1 h. The mixture was concentrated andthe residue poured into H₂O. The aqueous phase was extracted with EtOAcand the combined organic phases dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The crude product4-isopropyl-N-((3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide(1.00 g, 1.90 mmol, 62.6% yield, 69.7% purity) was used into the nextstep without further purification.

3-(4-Isopropylpyridin-2-yl)-N-(3-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution of4-isopropyl-N-((3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide (1.00 g, 1.90 mmol) in EtOH (20 mL) were added iodine(96 mg, 0.379 mmol) and hydrogen peroxide (129 mg, 3.79 mmol). Themixture was stirred at 15° C. for 1 h under N₂. The mixture was dilutedwith H₂O (30 mL) and saturated aqueous sodium sulfite (0.5 mL). Themixture was stirred at 0° C. for another 0.5 h and checked by potassiumiodide-starch test paper to see whether hydrogen peroxide was destroyed.The aqueous phase was extracted with EtOAc. The product was isolated andpurified via standard methods to give3-(4-isopropyl-2-pyridyl)-N-[3-(trifluoromethyl)-2-pyridyl]-1,2,4-thiadiazol-5-amine(373.04 mg, 0.975 mmol, 51.3% yield, 95.5% purity).

Example 11:3-(5-Isopropoxypyridin-2-yl)-N-(5-isopropyl-3-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

5-Bromo-3-(trifluoromethyl)pyridin-2-amine

To a mixture of 3-(trifluoromethyl)pyridin-2-amine (25 g, 154.21 mmol)in THE (250 mL) was added N-bromosuccinimide (27.45 g, 154.21 mmol) inportions at 0° C. Then the mixture was stirred at 15° C. for 1.5 h. Thereaction mixture was concentrated under reduced pressure to give a crudeproduct. The crude product was purified by column chromatography to give5-bromo-3-(trifluoromethyl)pyridin-2-amine (34.1 g, 141.49 mmol, 91.75%yield).

5-(Prop-1-en-2-yl)-3-(trifluoromethyl)pyridin-2-amine

To a mixture of 5-bromo-3-(trifluoromethyl)pyridin-2-amine (34.1 g,141.49 mmol), potassium trifluoro(prop-1-en-2-yl)borate (31.41 g, 212.23mmol), potassium carbonate (39.11 g, 282.98 mmol) in dioxane (500 mL)and H₂O (50 mL) was added[1,1-bis(diphenylphosphino)ferrocene]-dichloropalladium (2.07 g, 2.83mmol) under nitrogen. The mixture was stirred at 80° C. for 5 h. Themixture was filtered and the filtrate was concentrated and purified bycolumn chromatography to give5-isopropenyl-3-(trifluoromethyl)pyridin-2-amine (26.9 g, 133.05 mmol,94.04% yield).

5-Isopropyl-3-(trifluoromethyl)pyridin-2-amine

To the mixture 5-isopropenyl-3-(trifluoromethyl)pyridin-2-amine (26.9 g,133.05 mmol) in MeOH (150 mL) was added dry Pd/C (1.5 g, 10% purity) andwet hydroxide Pd/C (1.5 g, 20% purity) under nitrogen. The mixture wasdegassed under vacuum and purged with hydrogen several times. Themixture was stirred under hydrogen (15 psi) at 20° C. for 16 h. Themixture was filtered and the filtrate was concentrated to give5-isopropyl-3-(trifluoromethyl)pyridin-2-amine (26.7 g, 130.76 mmol,98.28% yield).

5-Isopropyl-2-isothiocyanato-3-(trifluoromethyl)pyridine

To a mixture of thiocarbonyl dichloride (5.07 g, 44.08 mmol, 3.38 mL) inDCM (50 mL) was added a solution of5-isopropyl-3-(trifluoromethyl)pyridin-2-amine (6 g, 29.38 mmol) in DCM(10 mL) at 0° C. under nitrogen. The mixture was stirred at 0° C. for 1h. The reaction mixture was quenched with saturated sodium bicarbonate(70 mL) at 0° C. The organic phase was separated and dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography to give5-isopropyl-2-isothiocyanato-3-(trifluoromethyl)pyridine (5.5 g, 21.22mmol, 72.21% yield, 95% purity).

5-Isopropoxy-N-((5-isopropyl-3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)Picolinimidamide

To the mixture 5-isopropoxypyridine-2-carboxamidine (363.89 mg, 2.03mmol) and 5-isopropyl-2-isothiocyanato-3-(trifluoromethyl)pyridine (0.5g, 2.03 mmol) in DCM (20 mL) and acetone (20 mL) was added TEA (616.38mg, 6.09 mmol, 0.85 mL). The mixture was stirred at 20° C. for 2 h. andconcentrated at reduced pressure to give a residue. H2O and saturatedsodium carbonate were added to the residue and the mixture was extractedwith EtOAc. The combined organic phases were dried over anhydrous sodiumsulfate, filtered and concentrated at reduced pressure to give5-isopropoxy-N-((5-isopropyl-3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide(484 mg, 1.02 mmol, 50.42% yield, 90% purity).

3-(5-Isopropoxypyridin-2-yl)-N-(5-isopropyl-3-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To the mixture of5-isopropoxy-N-((5-isopropyl-3-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide(484 mg, 1.02 mmol, 90% purity) and hydrogen peroxide (348.20 mg, 3.07mmol, 0.30 mL, 30% purity) in EtOH (20 mL) was added iodine (51.97 mg,0.21 mmol) at 0° C. The mixture was stirred at 20° C. for 0.5 h. Thereaction mixture was quenched with saturated sodium sulfite (10 mL) at0° C. The resulting mixture was concentrated to give a residue. Theproduct was isolated and purified via standard methods to give3-(5-isopropoxy-2-pyridyl)-N-[5-isopropyl-3-(trifluoromethyl)-2-pyridyl]-1,2,4-thiadiazol-5-amine(290.48 mg, 679.12 μmol, 66.33% yield); LCMS (ESI): m/z 424.2 [M+1]⁺.

Example 12:5-(5-Isopropoxypyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,3,4-thiadiazol-2-amine

5-Isopropoxypicolinohydrazide

To a solution of methyl 5-isopropoxypicolinate (600 mg, 3.07 mmol) inMeOH (6 mL) was added hydrazine hydrate (230 mg, 4.60 mmol). The mixturewas stirred at 70° C. for 5 h. The mixture was concentrated to give5-isopropoxypicolinohydrazide (600 mg, 2.83 mmol, 92% yield, 92%purity).

2-(5-Isopropoxypicolinoyl)-N-(3-methylpyridin-2-yl)hydrazinecarbothioamide

To a solution of 5-isopropoxypicolinohydrazide (500 mg, 2.36 mmol) inDCM (20 mL) was added 2-isothiocyanato-3-methylpyridine (532 mg, 3.54mmol). The mixture was stirred at 30° C. for 19 h. The mixture wasconcentrated. The residue was purified by prep-HPLC to give2-(5-isopropoxypicolinoyl)-N-(3-methylpyridin-2-yl)hydrazinecarbothioamide(130 mg, 0.376 mmol, 15.95% yield).

5-(5-Isopropoxypyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,3,4-thiadiazol-2-amine

To a solution of2-(5-isopropoxypicolinoyl)-N-(3-methylpyridin-2-yl)hydrazinecarbothioamide(160 mg, 0.463 mmol) in toluene (5 mL) was added p-toluenesulfonic acid(80 mg, 0.463 mmol). The mixture was stirred at 100° C. for 4 h. Themixture was concentrated. The product was isolated and purified viastandard methods to give5-(5-isopropoxypyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,3,4-thiadiazol-2-amine(89.15 mg, 0.237 mmol, 51% yield, 99.1% purity). LCMS (ESI): m/z 328.2[M+1]⁺.

Example13:5-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,3,4-thiadiazol-2-amine

2-(5-((1-Methylpiperidin-4-yl)oxy)picolinoyl)-N-(3-methylpyridin-2-yl)hydrazinecarbothioamide

To a solution of 5-((1-methylpiperidin-4-yl)oxy)picolinohydrazide (500mg, 1.98 mmol) in DCM (20 mL) was added2-isothiocyanato-3-methylpyridine (496 mg, 2.97 mmol). The mixture wasstirred at 30° C. for 19 h. The mixture was concentrated. The residuewas diluted with MeOH (5 mL). The solid was collected and dried in vacuoto give 150 mg of product. The filtrate was purified by prep-HPLC. Twoparts of products were combined and the solution was dried bylyophilization to give2-(5-((1-methylpiperidin-4-yl)oxy)picolinoyl)-N-(3-methylpyridin-2-yl)hydrazinecarbothioamide(300 mg, 0.749 mmol, 38% yield).

5-(5-((1-Methylpiperidin-4-yl)oxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,3,4-thiadiazol-2-amine

To a solution of2-(5-((1-methylpiperidin-4-yl)oxy)picolinoyl)-N-(3-methylpyridin-2-yl)hydrazinecarbothioamide(300 mg, 0.749 mmol) in toluene (20 mL) was added p-toluenesulfonic acid(129 mg, 0.749 mmol). The mixture was stirred at 100° C. for 6 h. Themixture was concentrated. The residue was diluted with saturated sodiumcarbonate and H₂O. The aqueous phase was extracted with EtOAc. Thecombined organic phase was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to give the crude product. Theproduct was isolated and purified via standard methods to give5-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,3,4-thiadiazol-2-amine(93.60 mg, 0.237 mmol, 32% yield, 96.8% purity). LCMS (ESI): m/z 383.1[M+1]⁺.

Example 14:N²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine

N-((3-(Dimethylamino)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide

To a solution of 5-isopropoxypyridine-2-carboxamidine (500 mg, 2.79mmol) in DCM (10 mL), acetone (10 mL) and TEA (2.82 g, 27.90 mmol) wasadded 2-isothiocyanato-N,N-dimethyl-pyridin-3-amine (500 mg, 2.79 mmol)under N₂. The mixture was stirred at 15° C. for 2 h under N₂. Themixture was concentrated. The residue was poured into H₂O (50 mL). Theaqueous phase was extracted with EtOAc. The combined organic phases weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to giveN-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide (1.10 g, crude).

N²-(3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine

To a solution ofN-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide (1.10 g, 3.08 mmol) in EtOH (10 mL) was added iodine (156 mg,0.616 mmol) and hydrogen peroxide (698 mg, 6.16 mmol, 30% purity) underN₂. The mixture was stirred at 15° C. for 1 h under N₂. The residue wasdiluted with H₂O and saturated aqueous sodium sulfite. The mixture wasstirred at 0° C. for another 0.5 h, the reaction was checked bypotassium iodide-starch test paper to see whether hydrogen peroxide wasdestroyed. The aqueous phase was extracted with EtOAc. The product wasisolated and purified via standard methods to giveN²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine(174.56 mg, 0.469 mmol, 15% yield, 95.8% purity). LCMS (ESI): m/z 357.1[M+1]⁺.

Example 15:(4-Methylpiperazin-1-yl)(6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)methanone

Methyl 6-carbamimidoylnicotinate Hydrochloride

To a solution of methyl 6-cyanonicotinate (3.00 g, 18.5 mmol) in MeOH(45 mL) was added sodium methoxide (200 mg, 3.70 mmol). The mixture wasstirred at 30° C. for 16 h. NH₄Cl (1.19 g, 22.2 mmol) was added, themixture was stirred at 70° C. for 4 h. The hot solution was filtered.The filtrate was concentrated to give a white solid. The white solid wastriturated with hot EtOH (30 mL). The mixture was filtered and thefiltrated was concentrated to give the crude product. The crude productwas triturated with DCM (30 mL) to give methyl 6-carbamimidoylnicotinatehydrochloride (2.30 g, 10.5 mmol, 57% yield, 98% purity).

Methyl 6-carbamimidoylnicotinate

To a solution of 6-carbamimidoylnicotinate hydrochloride (1.80 g, 8.35mmol) in MeOH (30 mL) was added Amberlyst A 26 (5.00 g) to adjust the pHto 10-11. The mixture was stirred at 15° C. for 3 h. The reactionmixture was filtered and concentrated. The residue was diluted with H₂O(20 mL) and dried by lyophilization to give 6-carbamimidoylnicotinate(900 mg, 4.87 mmol, 58% yield, 97% purity).

Methyl6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)nicotinate

To a solution of 2-isothiocyanato-3-methylpyridine (1.00 g, 6.66 mmol)in DCM (30 mL) and acetone (30 mL) were added methyl6-carbamimidoylnicotinate (1.19 g, 6.66 mmol) and TEA (6.74 g, 66.60mmol). The mixture was stirred at 15° C. for 16 h. The residue wasdiluted with H₂O and the aqueous phase was extracted with EtOAc. Thecombined organic phases were dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum to give methyl6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)nicotinate (2.50g, crude).

Methyl6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)nicotinate

To a solution of methyl6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)nicotinate (2.50g, 7.59 mmol) in EtOH (100 mL) were added iodine (385 mg, 1.52 mmol) andhydrogen peroxide (1.72 g, 15.2 mmol, 30% purity). The mixture wasstirred at 15° C. for 1 h. The mixture was cooled to 0° C. and quenchedwith saturated sodium sulfite (50 mL). The mixture was concentrated andthe residue was diluted with H₂O. The aqueous phase was extracted withEtOAc. The combined organic phases were dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum to give the crudeproduct. The crude product was triturated with ACN (20 mL) to give 650mg of product with 94% purity. The filtrate was concentrated and theresidue was purified by silica gel chromatography followed by prep-HPLCto give 150 mg of product. Two parts of products were combined to givemethyl6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)nicotinate (800mg, 2.44 mmol, 32% yield).

6-(5-((3-Methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)nicotinic Acid

To a solution of methyl6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)nicotinate (650mg, 1.87 mmol) in THE (60 mL) and H₂O (10 mL) was added lithiumhydroxide (785 mg, 18.70 mmol) at 0° C. The mixture was stirred at 15°C. for 2 h. The mixture was concentrated to remove the THF. The aqueousphase was adjusted to pH of approximately 5 with 2 N HCl and solid wasformed. The mixture was filtered, the solid was collected, and driedunder vacuum to give6-[5-[(3-methyl-2-pyridyl)amino]-1,2,4-thiadiazol-3-yl]pyridine-3-carboxylicacid (500 mg, 1.44 mmol, 77% yield, 90% purity).

(4-Methylpiperazin-1-yl)(6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)methanone

To a solution of6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)nicotinic acid(150 mg, 0.431 mmol), 1-methylpiperazine (86 mg, 0.861 mmol) and DIPEA(167 mg, 1.29 mmol) in DMF (3 mL) was added HATU (327 mg, 0.862 mmol) at0° C. The mixture was stirred at 30° C. for 5 h. The product wasisolated and purified via standard methods to give(4-methylpiperazin-1-yl)-[6-[5-[(3-methyl-2-pyridyl)amino]-1,2,4-thiadiazol-3-yl]-3-pyridyl]methanone(121.27 mg, 0.269 mmol, 63% yield, 98.0% purity). LCMS (ESI): m/z 396.1[M+1]⁺.

Example 16:3-(5-Methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

1′-Methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridine]-2-carbonitrile

To a mixture of 4-bromopicolinonitrile (1 g, 5.46 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,6-tetrahydropyridine(1.46 g, 6.55 mmol) in H₂O (16 mL) and dioxane (80 mL) were added sodiumcarbonate (1.45 g, 13.7 mmol) and palladium triphenylphosphine (316 mg,0.273 mmol) under nitrogen. The mixture was stirred at 80° C. for 16 h.The mixture was poured into H₂O. The aqueous phase was extracted withEtOAc. The combined organic phases were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by silica gel chromatography to give1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridine]-2-carbonitrile (1.8g, 9.03 mmol, 83% yield).

1′-Methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridine]-2-carboximidamidehydrochloride

To a solution of1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridine]-2-carbonitrile (1.30g, 6.52 mmol) in MeOH (65 mL) was added sodium methanolate (106 mg, 1.96mmol). The mixture was stirred at 25° C. for 16 h under nitrogen. NH₄Cl(698 mg, 13.0 mmol) was added into the above mixture. The mixture wasstirred at 70° C. for 4 h. The mixture was concentrated in vacuo and theresidue was triturated with DCM. The mixture was filtered and the filtercake was dried in vacuo to give1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridine]-2-carboximidamide;HCl salt (1.5 g, crude).

4-(1-Methylpiperidin-4-yl)picolinimidamide

To a solution of1′-methyl-1′,2′,3′,6′-tetrahydro-[4,4′-bipyridine]-2-carboximidamidehydrochloride (1.90 g, 7.52 mmol) in MeOH (50 mL) was added Pd/C (190mg, 15% purity). The mixture was stirred at 50° C. for 6 h underhydrogen balloon (15 psi). The mixture was filtered though celite andthe filtrate was concentrated in vacuo to give4-(1-methylpiperidin-4-yl)picolinimidamide hydrochloride (1.25 g,crude). The obtained compound in MeOH (50 mL) was adjusted to pH about10 by addition of Amberlyst A 26. The mixture was stirred at 25° C. for3 h. The reaction mixture was filtered and the filtrate was concentratedto give 4-(1-methylpiperidin-4-yl)picolinimidamide (1.25 g, crude),which was used directly in the next step.

4-(1-Methylpiperidin-4-yl)-N-((3-methylpyridin-2-yl)carbamothioyl)Picolinimidamide

To a mixture of 4-(1-methylpiperidin-4-yl)picolinimidamide (917 mg, 4.20mmol) and TEA (4.25 g, 42.0 mmol) in acetone (15 mL) and DCM (15 mL) wasadded 2-isothiocyanato-3-methylpyridine (757 mg, 5.04 mmol). The mixturewas stirred at 25° C. for 16 h under nitrogen. The mixture wasconcentrated in vacuo. The residue was diluted with H₂O (70 mL). Theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo to get the crude product. The crude product waspurified by prep-TLC to give a mixture of4-(1-methylpiperidin-4-yl)-N-((3-methylpyridin-2-yl)carbamothioyl)picolinimidamide and3-(4-(1-methylpiperidin-4-yl)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine(590 mg, 0.442 mmol, 21% yield, 55% purity).

3-(5-Methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution of5-methoxy-N-((5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2yl)carbamothioyl) picolinimidamide and3-(5-methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(490 mg, 0.367 mmol) in EtOH (25 mL) were added hydrogen peroxide (83.1mg, 0.733 mmol, 30% purity) and iodine (18.6 mg, 0.073 mmol). Themixture was stirred at 25° C. for 3 h. The residue was diluted with H₂O(50 mL) and saturated aqueous sodium sulfite (10 mL). The mixture wasstirred at 25° C. for another 0.5 h. The aqueous phase was extractedwith EtOAc. The product was isolated and purified via standard methodsto give3-(4-(1-methylpiperidin-4-yl)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine(277.82 mg, 0.645 mmol, 88% yield, 95.7% purity). LCMS (ESI): m/z 367.1[M+1]⁺.

Example 17:3-(5-Methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

2-Chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine

To a mixture of 6-chloropyridin-3-ol (2.00 g, 15.4 mmol) andtetrahydro-2H-pyran-4-ol (3.15 g, 30.88 mmol) in THE (60 mL) was addedPPh₃ (8.10 g, 30.9 mmol) at 0° C. under nitrogen. Then diisopropylazodicarboxylate (6.24 g, 30.9 mmol) was added into the above solutiondrop-wise at 0° C. The mixture was stirred at 25° C. for 20 h. Themixture was concentrated under reduced pressure. The residue waspurified by column to give2-chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (1.60 g, 7.49 mmol,49% yield).

N-(2,4-Dimethoxybenzyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-amine

To a mixture of 2-chloro-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (750mg, 3.51 mmol), (2,4-dimethoxyphenyl)methanamine (1.17 g, 7.02 mmol),dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (288 mg,0.702 mmol) and sodium 2-methylpropan-2-olate (675 mg, 7.02 mmol) intoluene (70 mL) was added palladium (II) acetate (79 mg, 0.351 mmol)under nitrogen. The mixture was stirred at 100° C. for 16 h. The mixturewas poured into H₂O (80 mL). The aqueous phase was extracted with EtOAc.The combined organic phases were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by column to giveN-(2,4-dimethoxybenzyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-amine(1.63 g, 4.21 mmol, 60% yield, 89% purity).

5-((Tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-amine

To a mixture ofN-(2,4-dimethoxybenzyl)-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-amine(1.43 g, 4.15 mmol) in DCM (2 mL) was added trifluoroacetic acid (3.08g, 2 mL) dropwise at 0° C. The mixture was stirred at 25° C. for 1 h.The mixture was concentrated in vacuo. The residue was adjusted withsaturated sodium bicarbonate (15 mL) to pH 8-9 and diluted with DCM (15mL). Precipitate was formed. The mixture was filtered and the filtercake was washed with DCM. The organic phase was separated and theaqueous phase was extracted with DCM. The combined organic phases werewashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by column to give5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-amine (800 mg, crude).

2-Isothiocyanato-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine

To a solution of di(1H-imidazol-1-yl)methanethione (433 mg, 2.43 mmol)in DMF (10 mL) was added a mixture of5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-amine (430 mg, 2.21 mmol) inDMF (5 mL) drop-wise. The mixture was stirred at 25° C. for 3 h.2-Isothiocyanato-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (512 mg, 2.17mmol, 98.19% yield) in DMF (15 mL) was obtained and used in the nextstep without purification.

5-Methoxy-N-((5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)carbamothioyl)picolinimidamide

To a mixture of2-isothiocyanato-5-((tetrahydro-2H-pyran-4-yl)oxy)pyridine (520 mg, 2.20mmol) in DMF (15 mL) were added 5-methoxypicolinimidamide (399 mg, 2.64mmol) and DIPEA (1.42 g, 11.0 mmol). The mixture was stirred at 40° C.for 16 h. The mixture was poured into H₂O (30 mL). The aqueous phase wasextracted with EtOAc. The combined organic phases were washed with H₂O.The combined aqueous phases were extracted with EtOAc. The combinedorganic phases were washed with brine, dried over anhydrous sodiumsulfate, filtered, and concentrated in vacuo to give a mixture of5-methoxy-N-((5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)carbamothioyl)picolinimidamideand3-(5-methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(816 mg, crude).

3-(5-Methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of5-methoxy-N-((5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)carbamothioyl)picolinimidamide and3-(5-methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(766 mg, crude) in EtOH (50 mL) was added hydrogen peroxide (449 mg,3.96 mmol) and iodine (101 mg, 0.396 mmol). The mixture was stirred at25° C. for 3 h. The product was isolated and purified via standardmethods to give3-(5-methoxypyridin-2-yl)-N-(5-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(357.45 mg, 0.916 mmol, 46% yield, 98.8% purity). LCMS (ESI): m/z 386.1[M+1]⁺.

Example 18:N-(6-(5-((3-Methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)acetamide

N-(6-Cyanopyridin-3-yl)acetamide

To a solution of 5-aminopicolinonitrile (1.00 g, 8.39 mmol) and TEA(2.55 g, 25.2 mmol) in DCM (50 mL) was added acetyl chloride (1.32 g,16.8 mmol) at 0° C. The mixture was stirred at 20° C. for 16 h. Themixture was diluted with 100 mL of DCM and washed with brine. Theorganic phase was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by flash column togive the crude product. The crude product was purified by prep-TLC togive N-(6-cyanopyridin-3-yl)acetamide (400 mg, crude).

N-(6-Carbamimidoylpyridin-3-yl)acetamide Hydrochloride

To a solution of N-(6-cyanopyridin-3-yl)acetamide (400 mg, 2.48 mmol) inMeOH (10 mL) was added sodium methoxide (40 mg, 0.744 mmol). The mixturewas stirred at 40° C. for 16 h. NH₄Cl (172 mg, 3.22 mmol) was added tothe mixture, and the mixture was stirred at 70° C. for 4 h. The mixturewas concentrated, and the residue was diluted with 20 mL of EtOH, theresulting mixture was refluxed for 0.5 h. The mixture was filtered andthe filtrate was concentrated. The residue was triturated with DCM (20mL) to give N-(6-carbamimidoylpyridin-3-yl)acetamide hydrochloride (500mg, crude).

N-(6-Carbamimidoylpyridin-3-yl)acetamide

To a solution of N-(6-carbamimidoylpyridin-3-yl)acetamide hydrochloride(400 mg, 1.86 mmol) in MeOH (20 mL) was added Amberlyst A 26 (2.5 g).The mixture was stirred at 25° C. for 2 h. The reaction mixture wasfiltered and the filtrate was concentrated to giveN-(6-carbamimidoylpyridin-3-yl)acetamide (280 mg, crude).

N-(6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)pyridin-3-yl)Acetamide

To a solution of N-(6-carbamimidoylpyridin-3-yl)acetamide (280 mg, 1.57mmol) and 2-isothiocyanato-3-methylpyridine (354 mg, 2.36 mmol) in DCM(15 mL) and acetone (15 mL) was added TEA (794 mg, 7.85 mmol). Themixture was stirred at 25° C. for 3 h. The mixture was concentrated. Theresidue was diluted with 30 mL of H₂O, the aqueous phase was extractedwith EtOAc. The combined organic phases were dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified by prep-TLC to giveN-(6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)pyridin-3-yl)acetamide (200 mg, crude).

N-(6-(5-((3-Methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)pyridin-3-yl)Acetamide

To a solution ofN-(6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)pyridin-3-yl)acetamide (200 mg, 0.609 mmol) in THE (10 mL) was addeddiisopropyl azodiformate (184 mg, 0.914 mmol). The mixture was stirredat 25° C. for 2 h. The product was isolated and purified via standardmethods to giveN-[6-[5-[(3-methyl-2-pyridyl)amino]-1,2,4-thiadiazol-3-yl]-3-pyridyl]acetamide(50.72 mg, 0.148 mmol, 24% yield, 95.5% purity). LCMS (ESI): m/z 327.1[M+1]⁺.

Example 19:3-(5-Isopropoxypyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

5-Isopropoxypicolinonitrile

To a solution of propan-2-ol (1.18 g, 19.7 mmol, 1.49 mL) inN,N-dimethylformamide (40 mL) was added NaH (983 mg, 24.6 mmol, 60%purity) at 0° C. under nitrogen. The mixture was stirred at 25° C. for30 min. Then 5-fluoropicolinonitrile (2.00 g, 16.4 mmol) was added tothe reaction mixture at 0° C. under nitrogen. The mixture was stirred at25° C. for 4 h. The mixture was poured into cold H₂O. The aqueous phasewas extracted with EtOAc. The organic layers were washed with brine,dried over sodium sulfate, filtered, and concentrated to give a residue.The residue was purified by silica gel chromatography to give5-isopropoxypicolinonitrile (2.10 g, crude).

5-Isopropoxypicolinimidamide

To a solution of 5-isopropoxypicolinonitrile (500 mg, 3.08 mmol) in MeOH(25 mL) was added sodium methanolate (16.6 mg, 308 μmol). The mixturewas stirred at 25° C. for 8 h. NH₄Cl (330 mg, 6.16 mmol) was added tothe mixture and refluxed at 70° C. for 4 h. The mixture was concentratedunder reduced pressure to give a residue. The residue was trituratedwith DCM (30 mL). The mixture was filtered, and the filter cake wasdried to remove the solvent to give 5-isopropoxypicolinimidamidehydrochloride (800 mg, crude).

2-Isothiocyanato-3-methylpyridine

To a solution of thiophosgene (5.32 g, 46.2 mmol) in DCM (80 mL) wasadded a solution of 3-methylpyridin-2-amine (5 g, 46.2 mmol) in DCM (50mL) at −5° C. under nitrogen atmosphere. The mixture was stirred at 25°C. for 3 h. Saturated sodium bicarbonate was added to the mixture. Themixture was extracted with DCM. The combined organic layers were driedover sodium sulfate, filtered, and concentrated under reduced pressureto give a residue. The residue was purified by silica gel columnchromatography to give 2-isothiocyanato-3-methylpyridine (1.00 g, 6.66mmol, 14% yield).

5-Isopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)picolinimidamide

To a solution of 2-isothiocyanato-3-methylpyridine (557 mg, 3.71 mmol)and TEA (3.75 g, 37.1 mmol, 5.14 mL) in DCM (15 mL) and acetone (15 mL)was added 5-isopropoxypicolinimidamide hydrochloride (800 mg, 3.71mmol). The mixture was stirred at 25° C. for 20 h. The reaction mixturewas concentrated under reduced pressure, diluted with H₂O, and extractedwith EtOAc. The combined organic layers were washed with brine, driedover sodium sulfate, filtered, and concentrated under reduced pressureto give 5-isopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)picolinimidamide (350 mg, crude).

3-(5-Isopropoxypyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution of5-isopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)picolinimidamide(350 mg, 1.06 mmol) in THE (10 mL) was added diisopropyl azodiformate(279 mg, 1.38 mmol). The mixture was stirred at 25° C. for 20 h. Theproduct was isolated and purified via standard methods to give3-(5-isopropoxypyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine(126 mg, 0.385 mmol, 36% yield, 99.3% purity). LCMS (ESI): m/z 328.2[M+1]⁺.

Example 20:N,N-Dimethyl-6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)Nicotinamide

6-Cyano-N,N-dimethylnicotinamide

To a solution of 6-cyanonicotinic acid (1.00 g, 6.75 mmol),N-methylmethanamine hydrochloride (605 mg, 7.43 mmol) and DIPEA (2.62 g,20.3 mmol) in DCM (50 mL) was added HATU (3.08 g, 8.10 mmol) at 0° C.The mixture was stirred at 20° C. for 16 h. The mixture was concentratedand purified by flash column to give 6-cyano-N,N-dimethylnicotinamide(1.00 g, crude).

6-Carbamimidoyl-N,N-dimethylnicotinamide hydrochloride

To a solution of 6-cyano-N,N-dimethylnicotinamide (500 mg, 2.85 mmol) inMeOH (10 mL) was added sodium methoxide (31 mg, 0.571 mmol). The mixturewas stirred at 20° C. for 16 h. NH₄Cl (183 mg, 3.42 mmol) was added tothe solution, and the mixture was stirred at 70° C. for 4 h. The mixturewas concentrated and triturated with DCM (20 mL) to give6-carbamimidoyl-N,N-dimethylnicotinamide hydrochloride (500 mg, crude).

N,N-Dimethyl-6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)-nicotinamide

To a solution of 2-isothiocyanato-3-methylpyridine (300 mg, 2.00 mmol)and TEA (2.02 g, 20.0 mmol) in DCM (20 mL) and acetone (20 mL) was added6-carbamimidoyl-N,N-dimethylnicotinamide hydrochloride (457 mg, 2.00mmol). The mixture was stirred at 20° C. for 16 h. The mixture wasconcentrated and purified by prep-TLC to giveN,N-dimethyl-6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)nicotinamide(300 mg, crude).

N,N-Dimethyl-6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)Nicotinamide

To a solution of N,N-dimethyl-6-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)nicotinamide (300 mg, 0.876 mmol) in THE (15 mL) was addeddiisopropyl azodiformate (177 mg, 0.876 mmol). The mixture was stirredat 20° C. for 2 h. The mixture was concentrated. The product wasisolated and purified via standard methods to giveN,N-dimethyl-6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)nicotinamide(158.80 mg, 0.462 mmol, 52% yield, 99% purity). LCMS (ESI): m/z 341.1[M+1]⁺.

Example 21:N³-methyl-N²-(3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine

tert-butyl-(2-Nitropyridin-3-yl)carbamate

To a solution of 2-nitropyridin-3-amine (2.00 g, 14.4 mmol) in TH (30mL) was added 1,1,1-trimethyl-n-(trimethylsilyl)-silanamin sodium (1 M,21.6 mL) at 0° C. The mixture was stirred at 20° C. for 1 h. Thendi-tert-butyl dicarbonate (3.45 g, 15.8 mmol) in THF (20 mL) was addedat 0° C. The mixture was stirred at 25° C. for 16 h. The mixture waspoured into cold H₂O. The aqueous phase was extracted with EtOAc. Thecombined organic phases were washed with brine, dried over anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography to give tert-butyl(2-nitropyridin-3-yl) carbamate (2.00 g, 8.36 mmol, 58% yield).

tert-butyl-methyl-(2-nitropyridin-3-yl)carbamate

To a solution of tert-butyl (2-nitropyridin-3-yl) carbamate (2.00 g,8.36 mmol) in DMF (30 mL) was added NaH (501 mg, 12.5 mmol, 60% purity)at 0° C. The mixture was stirred at 25° C. for 0.5 h. Iodomethane (1.54g, 10.9 mmol) was added at 0° C., the mixture was stirred at 25° C. for2 h. The residue was poured into cold H₂O. The aqueous phase wasextracted with EtOAc (300 mL). The organic phase was washed with brine,dried over anhydrous sodium sulfate, filtered, and concentrated undervacuum. The residue was purified by silica gel chromatography to givetert-butyl methyl-(2-nitropyridin-3-yl)carbamate (1.80 g, crude).

tert-butyl-(2-aminopyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl methyl-(2-nitropyridin-3-yl)carbamate (1.80g, 7.11 mmol) in MeOH (40 mL) was added wet Pd/C (300 mg). The mixturewas stirred at 25° C. for 1 h under H₂ (15 psi). The reaction mixturewas filtered and the filtrate was concentrated to give tert-butyl(2-aminopyridin-3-yl)-(methyl)-carbamate (1.40 g, 6.27 mmol, 88% yield).

tert-butyl-(2-isothiocyanatopyridin-3-yl)(methyl)carbamate

To a solution of thiocarbonyl dichloride (1.03 g, 8.96 mmol) in DCM (20mL) was added a mixture of tert-butyl(2-aminopyridin-3-yl)(methyl)carbamate (1.00 g, 4.48 mmol) in DCM (20mL) at −5° C. The mixture was stirred at 25° C. for 2 h. The mixture wasdiluted with 50 mL of DCM. The organic phase was washed with sodiumbicarbonate, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography to give tert-butyl(2-isothiocyanatopyridin-3-yl)-(methyl)carbamate (700 mg, crude).

tert-butyl-(2-(3-(imino(4-methylpyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(2-isothiocyanatopyridin-3-yl)-(methyl)-carbamate (400 mg, 1.51 mmol)and TEA (1.53 g, 15.1 mmol) in DCM (20 mL) and acetone (20 mL) was added4-methylpicolinimidamide hydrochloride (259 mg, 1.51 mmol). The mixturewas stirred at 25° C. for 16 h. The mixture was concentrated and theresidue was diluted with 30 mL of H₂O. The aqueous phase was extractedwith DCM. The combined organic phases were dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified by prep-TLC to give tert-butyl(2-(3-(imino-(4-methylpyridin-2-yl)methyl)-thioureido)pyridin-3-yl)(methyl)carbamate(400 mg, crude).

tert-butyl-methyl-(2-((3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate

To a solution of tert-butyl(2-(3-(imino-(4-methylpyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate (400 mg, 0.999 mmol) in THE (2 mL) was added diisopropylazodiformate (202 mg, 0.999 mmol). The mixture was stirred at 25° C. for2 h. The mixture was diluted with 100 mL of EtOAc. The organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to give tert-butylmethyl(2-((3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(500 mg, crude).

N³-methyl-N²-(3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine

To a solution of tert-butylmethyl-(2-((3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(400 mg, 1.00 mmol) in DCM (6 mL) was added trifluoroacetic acid (3 mL)at 0° C. The mixture was stirred at 25° C. for 2 h and concentrated at25° C. The product was isolated and purified via standard methods togiveN³-methyl-N²-(3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diaminetrifluoroacetate (50.10 mg, 0.116 mmol, 12% yield, 95.1% purity). LCMS(ESI): m/z 299.3 [M+1]⁺.

Example 22:N-(3-Methoxypyridin-2-yl)-3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

2-Iothiocyanato-3-methoxypyridine

To a solution of thiocarbonyl dichloride (1.11 g, 9.66 mmol) in DCM (10mL) was added a solution of 3-methoxypyridin-2-amine (600 mg, 4.83 mmol)in DCM (5 mL) dropwise at −5° C. under N₂. The mixture was stirred at25° C. for 3 h under N₂. Saturated sodium bicarbonate solution was addedto the mixture, the aqueous phase was extracted with DCM. The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated under reduced pressure to give a residue. The residue waspurified by silica gel chromatography to give2-isothiocyanato-3-methoxy-pyridine (160 mg, 0.97 mmol, 20% yield).

N-((3-Methoxypyridin-2-yl)carbamothioyl)-4-methylpicolinimidamide

To a solution of 2-isothiocyanato-3-methoxy-pyridine (160 mg, 0.963mmol) in DCM (15 mL) and acetone (15 mL) was added TEA (2.19 g, 21.64mmol) and 4-methylpyridine-2-carboxamidine hydrochloride (215 mg, 1.25mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixturewas quenched with H₂O (30 mL). The aqueous phase was extracted withEtOAc. The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated under reduce pressure to give aresidue. The residue was purified by prep-TLC (SiO₂, petroleumether/EtOAc=1/1) to give N-((3-methoxypyridin-2-yl)carbamothioyl)-4-methylpicolinimidamide (180 mg, crude).

N-(3-Methoxypyridin-2-yl)-3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution of N-((3-methoxypyridin-2-yl) carbamothioyl)-4-methylpicolinimidamide (180 mg, 0.597 mmol) in THE (10 mL) was addeddiisopropyl azodiformate (121 mg, 0.597 mmol). The mixture was stirredat 25° C. for 2 h. The product was isolated and purified via standardmethods to giveN-(3-methoxy-2-pyridyl)-3-(4-methyl-2-pyridyl)-1,2,4-thiadiazol-5-amine(49.8 mg, 0.165 mmol, 27% yield, 99% purity). LCMS (ESI): m/z 300.1[M+1]⁺.

Example 23:N-(3-Fluoropyridin-2-yl)-3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

3-Fluoro-2-isothiocyanatopyridine

To a solution of 3-fluoropyridin-2-amine (2.00 g, 17.8 mmol) in DCM (40mL) was added DIPEA (4.61 g, 35.7 mmol) at 25° C. Thiophosgene (2.05 g,17.8 mmol) was added slowly into the reaction mixture at 0° C. Thereaction mixture was stirred at 25° C. for 16 h. The reaction mixturewas concentrated under reduced pressure to give a residue. The residuewas purified by silica gel chromatography to give3-fluoro-2-isothiocyanatopyridine (340 mg, crude).

4-Methylpicolinimidamide Hydrochloride

To a solution of 4-methylpicolinonitrile (1.00 g, 8.46 mmol) in MeOH (20mL) was added sodium methanolate (46 mg, 0.846 mmol). The mixture wasstirred at 25° C. for 20 h. NH₄Cl (498 mg, 9.31 mmol) was added to themixture. The mixture was stirred at 70° C. for 4 h. The mixture wasconcentrated under reduced pressure to give a residue. The residue wasrefluxed for 30 min in EtOH (30 mL). The hot solution was filtered andthe cake washed with EtOH. The filtrate was evaporated in vacuo to give4-methylpicolinimidamide hydrochloride (1.30 g, crude).

N-((3-Fluoropyridin-2-yl)carbamothioyl)-4-methylpicolinimidamide

To a solution of 4-methylpicolinimidamide hydrochloride (379 mg, 2.21mmol) and TEA (670 mg, 6.62 mmol) in DCM (10 mL) and acetone (10 mL) wasadded 3-fluoro-2-isothiocyanatopyridine (340 mg, 2.21 mmol). The mixturewas stirred at 25° C. for 20 h. The reaction mixture was concentratedunder reduced pressure to give a residue. The residue was diluted withH₂O and extracted with EtOAc. The combined organic layers were washedwith brine, dried over sodium sulfate, filtered, and concentrated underreduced pressure to give a residue. The residue was purified by silicagel chromatography to giveN-((3-fluoropyridin-2-yl)carbamothioyl)-4-methylpicolinimidamide (200mg, crude).

N-(3-Fluoropyridin-2-yl)-3-(4-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution of1-(3-fluoro-2-pyridyl)-3-(4-methylpyridine-2-carboximidoyl)thiourea (100mg, 346 μmol) in THE (8 mL) was added diisopropyl azodiformate (60 mg,0.297 mmol). The mixture was stirred at 25° C. for 20 h. The product wasisolated and purified via standard methods to giveN-(3-fluoro-2-pyridyl)-3-(4-methyl-2-pyridyl)-1,2,4-thiadiazol-5-amine(35.47 mg, 0.104 mmol, 30% yield, 98.5% purity). LCMS (ESI): m/z 288.1[M+1]⁺.

Example 24:N-(3-(5-Isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-yl)-3-methylpyridin-2-amine

1-(3-Methylpyridin-2-yl)thiourea

To a solution of 2-isothiocyanato-3-methyl-pyridine (1.50 g, 8.99 mmol)in DCM (15 mL) was added ammonium hydroxide (3.78 g, 26.9 mmol, 25%purity). The mixture was stirred at 30° C. for 1 h. The mixture wasconcentrated in vacuo. The residue was diluted with H₂O and the aqueousphase was extracted with DCM. The combined organic phases were driedover anhydrous sodium sulfate, filtered, and concentrated under vacuumto give 1-(3-methylpyridin-2-yl)thiourea (1.00 g, 4.73 mmol, 52.6%yield, 79.1% purity).

Methyl (3-methylpyridin-2-yl)carbamimidothioate

To a solution of 1-(3-methylpyridin-2-yl)thiourea (1.10 g, 5.20 mmol) inACN (10 mL) was added iodomethane (960 mg, 6.76 mmol). The mixture wasstirred at 40° C. for 16 h. The mixture was concentrated. The residuewas diluted with H₂O, and the aqueous phase was adjusted to pH of 8 withsaturated sodium bicarbonate. The aqueous phase was extracted with EtOAcand the combined organic phases were dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified by column chromatography to give methyl (3-methylpyridin-2-yl)carbamimidothioate (450 mg, 2.13 mmol, 41% yield, 85.7% purity).

N-(3-(5-Isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-yl)-3-methylpyridin-2-amine

To a solution of methyl (3-methylpyridin-2-yl)carbamimidothioate (250mg, 1.38 mmol) in pyridine (5 mL) was added5-isopropoxypyridine-2-carbohydrazide (269 mg, 1.38 mmol). The mixturewas stirred at 120° C. for 16 h. The product was isolated and purifiedvia standard methods to give N-(3-(5-isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-yl)-3-methylpyridin-2-amine (127.08 mg,0.400 mmol, 29% yield, 98.8% purity). LCMS (ESI): m/z 311.3 [M+1]⁺.

Example 25:3-Methyl-N-(3-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)pyridin-2-amine

5-((1-Methylpiperidin-4-yl)oxy)picolinic Acid

To a solution of 5-((1-methylpiperidin-4-yl)oxy)picolinonitrile (4.70 g,21.6 mmol) in EtOH (80 mL) and H₂O (20 mL) was added sodium hydroxide(6.06 g, 151.41 mmol). The mixture was stirred at 80° C. for 16 h. Themixture was concentrated and the residue was diluted with 50 mL of H₂O.The aqueous phase was adjusted to pH of 6 with 6 N HCl and the aqueousphase was concentrated to give a white solid. The solid was trituratedwith MeOH (100 mL). The filtrate was concentrated to give5-((1-methylpiperidin-4-yl)oxy)picolinic acid (10.0 g, crude).

Methyl 5-((1-methylpiperidin-4-yl)oxy)picolinate

To a solution of 5-((1-methylpiperidin-4-yl)oxy)picolinic acid (10.0 g,42.3 mmol) in MeOH (100 mL) was added thionyl chloride (15.1 g, 127mmol) at 10° C. The mixture was stirred at 70° C. for 3 h. The mixturewas concentrated and the residue was diluted with 50 mL of H₂O. Theaqueous phase was adjusted to pH of 8 with saturated sodium bicarbonateand extracted with EtOAc. The combined organic phases were dried overanhydrous sodium sulfate, filtered, and concentrated in vacuum to givemethyl 5-((1-methylpiperidin-4-yl)oxy)picolinate (500 mg, 1.97 mmol, 5%yield, 98.4% purity).

5-((1-Methylpiperidin-4-yl)oxy)picolinohydrazide

To a solution of methyl methyl 5-((1-methylpiperidin-4-yl)oxy)picolinate(500 mg, 2.00 mmol) in MeOH (5 mL) was added hydrazine hydrate (150 mg,3.00 mmol). The mixture was stirred at 70° C. for 3 h. Hydrazine hydrate(100 mg, 2.00 mmol) was added to the above mixture. The mixture wasstirred at 70° C. for 1 h. The reaction was concentrated in vacuo togive 5-((1-methylpiperidin-4-yl)oxy)picolinohydrazide (500 mg, 2.00mmol, 99.8% yield).

3-Methyl-N-(3-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)pyridin-2-amine

To a solution of 2-methyl-N-(3-methyl-2-pyridyl)isothiourea (270 mg,1.27 mmol) in pyridine (5 mL) was added5-[(1-methyl-4-piperidyl)oxy]pyridine-2-carbohydrazide (317 mg, 1.27mmol). The mixture was stirred at 120° C. for 16 h. The product wasisolated and purified via standard methods to give3-methyl-N-(3-(5-((1-methylpiperidin-4-yl)oxy)pyridin-2-yl)-1H-1,2,4-triazol-5-yl)pyridin-2-amine(53.73 mg, 0.125 mmol, 10% yield, 95.6% purity). LCMS (ESI): m/z 366.1[M+1]⁺.

Example 26:N-(3-(5-Isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-yl)-3-(trifluoromethyl)pyridine-2-amine

Methyl 5-hydroxypicolinate

To a mixture of 5-hydroxypicolinic acid (16.00 g, 115 mmol) and DMF (84mg, 1.15 mmol) in MeOH (150 mL) was added thionyl chloride (41.05 g,345.06 mmol) at 10° C. The mixture was stirred at 80° C. for 4 h.Thionyl chloride (6.84 g, 57.51 mmol) was added to the above mixture andstirred at 80° C. for 2 h. The mixture was concentrated and the residuewas diluted with H₂O. The aqueous phase was adjusted to pH of 8 withsaturated sodium bicarbonate. A solid formed, the solid was collectedand dried in vacuo to give methyl 5-hydroxypicolinate (12.80 g, 83.6mmol, 73% yield).

Methyl 5-isopropoxypicolinate

To a mixture of methyl 5-hydroxypicolinate (6.00 g, 39.2 mmol) in DMF(20 mL) and ACN (100 mL) were added potassium carbonate (16.25 g, 117.54mmol) and 2-bromopropane (14.46 g, 117.54 mmol). The mixture was stirredat 80° C. for 16 h under N₂. The mixture was diluted with ACN (100 mL).The mixture was filtered and the filtrate was concentrated to givemethyl 5-isopropoxypicolinate (7.10 g, 36.4 mmol, 93% yield).

5-Isopropoxypicolinohydrazide

To a solution of methyl 5-isopropoxypicolinate (9.00 g, 46.1 mmol) inMeOH (60 mL) was added hydrazine hydrate (3.53 g, 69.2 mmol, 98%purity). The mixture was stirred 70° C. at for 1 h. The reaction wasconcentrated in vacuo to give 5-isopropoxypicolinohydrazide (9.00 g,45.5 mmol, 99% yield, 98.7% purity).

2-(5-Isopropoxypicolinoyl)hydrazinecarboximidamide

The mixture of 5-isopropoxypicolinohydrazide (8.00 g, 40.5 mmol) and2-methylisothiourea; sulfuric acid (11.3 g, 40.5 mmol) in H₂O (80 mL)was stirred at 100° C. for 16 h. The mixture was concentrated to give asolid. The solid was triturated with EtOH (30 mL) to give2-(5-isopropoxypicolinoyl)hydrazinecarboximidamide (9.60 g, 38.2 mmol,94% yield, 94.4% purity).

3-(5-isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-amine

To a solution of sodium hydroxide (3.06 g, 76.4 mmol) in H₂O (96 mL) wasadded 2-(5-isopropoxypicolinoyl)-hydrazinecarboximidamide (9.60 g, 38.20mmol). The mixture was stirred at 100° C. for 6 h. and then neutralizedwith hydrogen chloride (6 N) to a pH of 6-7. The mixture was filteredand the filter cake was washed with EtOH (0.5 mL) to give3-(5-isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-amine (5.60 g, 25.3mmol, 66% yield, 99.0% purity).

3-(5-Isopropoxypyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine

To a solution of 3-(5-isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-amine(500 mg, 2.28 mmol) in DMF (20 mL) was added NaH (228 mg, 5.70 mmol, 60%purity) at 0° C. under N₂. The mixture was stirred at 10° C. for 1 h.(2-(Chloromethoxy)ethyl)trimethylsilane (380 mg, 2.28 mmol) was thenadded at −20° C. The mixture was stirred at 0° C. for 1 h. The mixturewas quenched with H₂O and the resultant mixture was extracted with EtOAcand the combined organic phases were dried over sodium sulfate,filtered, and concentrated under reduced pressure to give a residue (1.0g). The residue (0.8 g) was purified by prep-HPLC to give3-(5-isopropoxypyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-amine(90 mg, 0.260 mmol, 11% yield).

N-(3-(5-Isopropoxypyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(trifluoromethyl)pyridin-2-amine

To a solution of3-(5-isopropoxypyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-aminein DMF (2 mL) was added NaH (41 mg, 1.03 mmol, 60% purity) at 0° C. Themixture was stirred at 25° C. for 0.5 h. Then a solution of2-fluoro-3-(trifluoromethyl)pyridine (51 mg, 0.31 mmol) in DMF (1 mL)was added at 0° C. The mixture was stirred at 25° C. for 2 h and theresidue was poured into cold H₂O. The aqueous phase was extracted withEtOAc. The combined organic phases were washed with brine, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum togiveN-(3-(5-isopropoxypyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(trifluoromethyl)pyridin-2-amine(130 mg, crude).

N-(3-(5-Isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-yl)-3-(trifluoromethyl)pyridine-2-amine

To a solution ofN-(3-(5-isopropoxypyridin-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-1,2,4-triazol-5-yl)-3-(trifluoromethyl)pyridin-2-amine (130mg, 0.260 mmol) in EtOAc (3 mL) was added HCl/EtOAc (4 M, 6.6 mL). Themixture was stirred at 25° C. for 1 h. The product was isolated andpurified via standard methods to giveN-(3-(5-isopropoxypyridin-2-yl)-1H-1,2,4-triazol-5-yl)-3-(trifluoromethyl)pyridine-2-amine(59.45 mg, 0.161 mmol, 61% yield, 98.7% purity). LCMS (ESI): m/z 365.1[M+1]⁺.

Example 27:3-(3-Fluoropyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-5amine

3-Fluoro-N-hydroxypicolinimidamide

To a solution of 3-fluoropicolinonitrile (1.0 g, 8.19 mmol) in EtOH (20mL) were added hydroxylamine hydrochloride (1.14 g, 16.4 mmol) and TEA(1.66 g, 16.4 mmol, 2.27 mL). The mixture was stirred at 70° C. for 16h. The mixture was concentrated under reduced pressure to give aresidue. The residue was diluted with EtOAc (60 mL) and washed with H₂O(10 mL). The aqueous phase was extracted with EtOAc. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated to give 3-fluoro-N-hydroxypicolinimidamide (1.20 g, crude).

3-(3-Fluoropyridin-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole

To a solution of 3-fluoro-N-hydroxypicolinimidamide (1.20 g, 7.74 mmol)in toluene (50 mL) was added 2,2,2-trichloroacetic anhydride (4.78 g,15.5 mmol). The mixture was stirred at 110° C. for 4 h. The mixture wasconcentrated under reduced pressure to give a residue. The residue wasdiluted with EtOAc (60 mL), washed with sodium bicarbonate (20 mL). Theaqueous phase was extracted with EtOAc. The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated to givea crude product. The crude product was purified by silica gelchromatography to give3-(3-fluoropyridin-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (1.70 g,5.84 mmol, 75% yield, 97% purity).

3-(3-Fluoropyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-5-amine

To a solution of 4-(trifluoromethyl)pyridin-2-amine (460 mg, 2.83 mmol)in THE (20 mL) was added NaH (211 mg, 60% purity) slowly at 0° C. Themixture was stirred at 25° C. for 0.5 h under nitrogen. Then a solutionof 3-(3-fluoropyridin-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (1.0 g,3.54 mmol) in THF (8 mL) was added to the reaction mixture at 0° C. Thereaction mixture was stirred at 25° C. for 2 h under nitrogen. Theproduct was isolated and purified via standard methods to give3-(3-fluoropyridin-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)-1,2,4-oxadiazol-5-amine(132.72 mg, 0.406 mmol, 12% yield, 99.45% purity). LCMS (ESI): m/z 326.1[M+1]⁺.

Example 28:3-(3-Methylpyridin-2-yl)-N-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1,2,4-oxadiazol-5-amine

N-Hydroxy-3-methylpicolinimidamide

To a solution of 3-methylpyridine-2-carbonitrile (1.00 g, 8.46 mmol) andTEA (1.71 g, 16.92 mmol) in EtOH (15 mL) was added NH₂OH.HCl (559 mg,16.92 mmol). The mixture was stirred at 80° C. for 16 h. The reactionmixture was concentrated under reduced pressure to give a residue. Theresidue was diluted with H₂O (20 mL) and the aqueous layer was extractedwith EtOAc. The combined organic layers were dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to giveN-hydroxy-3-methyl-pyridine-2-carboxamidine (1.20 g, 7.86 mmol, 93%yield, 99% purity).

3-(3-Methylpyridin-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole

To a solution of N-hydroxy-3-methyl-pyridine-2-carboxamidine (1.20 g,7.94 mmol) in toluene (30 mL) was added trichloroacetic anhydride (4.90g, 15.88 mmol). The mixture was stirred at 110° C. for 3 h under N₂. Thereaction mixture was concentrated under reduced pressure to give aresidue. The residue was diluted with H₂O and extracted with EtOAc. Thecombined organic phases were washed with saturated sodium bicarbonate,dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure to give a residue. The residue was purified by columnchromatography to give3-(3-methyl-2-pyridyl)-5-(trichloromethyl)-1,2,4-oxadiazole (2.10 g,7.22 mmol, 91% yield, 95.8% purity).

2-Nitro-5-(pyrrolidin-1-yl)pyridine

A solution of 5-bromo-2-nitro-pyridine (500 mg, 2.46 mmol) andpyrrolidine (8.76 g, 123.16 mmol) were combined in a microwave tube. Thesealed tube was heated at 120° C. for 1 h under microwave. The residuewas poured into H₂O. The aqueous phase was extracted with EtOAc. Theorganic phase was dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was triturated with petroleumether:EtOAc (1:1, 40 mL) and filtered, and the filter cake was dried togive 2-nitro-5-pyrrolidin-1-yl-pyridine (2.80 g, 13.8 mmol, 56% yield,95.1% purity).

5-(Pyrrolidin-1-yl)pyridin-2-amine

To a solution of 2-nitro-5-pyrrolidin-1-yl-pyridine (2.80 g, 14.49 mmol)in MeOH (30 mL) was added Pd/C (560 mg, 10% purity). The suspension wasdegassed under vacuum and purged with H₂ several times. The mixture wasstirred under H₂ (15 psi) at 25° C. for 2 h. The reaction mixture wasfiltered and the filtrate was concentrated. The residue was dried bylyophilization to give 5-pyrrolidin-1-ylpyridin-2-amine (1.70 g, 8.56mmol, 59% yield, 82.2% purity).

3-(3-Methylpyridin-2-yl)-N-(5-(pyrrolidin-1-yl)pyridin-2-yl)-1,2,4-oxadiazol-5-amine

To a solution of 5-pyrrolidin-1-ylpyridin-2-amine (293 mg, 1.80 mmol) inTHE (10 mL) was added n-BuLi (2.5 M, 0.72 mL) at −70° C. under N₂. Themixture was stirred at −70° C. for 1 h. A solution of3-(3-methyl-2-pyridyl)-5-(trichloromethyl)-1,2,4-oxadiazole (500 mg,1.80 mmol) in THE (5 mL) was added into above mixture. The reaction wasstirred at −20° C. for 2 h. The product was isolated and purified viastandard methods to give3-(3-methyl-2-pyridyl)-N-(5-pyrrolidin-1-yl-2-pyridyl)-1,2,4-oxadiazol-5-amine(139.78 mg, 0.430 mmol, 24% yield, 99.1% purity). LCMS (ESI): m/z 323.3[M+1]⁺

Example 29:3-(5-Methoxypyridin-2-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-oxadiazol-5-amine

5-Methoxypicolinonitrile

To a mixture of 5-hydroxypicolinonitrile (1.00 g, 8.33 mmol) andpotassium carbonate (2.30 g, 16.7 mmol) in DMF (15 mL) was addediodomethane (1.77 g, 12.5 mmol) at 25° C. The mixture was stirred at 25°C. for 24 h. The mixture was poured into H₂O and the aqueous phase wasextracted with EtOAc. The combined organic phases were washed withbrine, dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to give a residue. The residue was purified by silica gelchromatography to give 5-methoxypicolinonitrile (750 mg, 5.54 mmol, 66%yield, 99% purity).

N-Hydroxy-5-methoxypicolinimidamide

To a solution of 5-methoxypicolinonitrile (750 mg, 5.54 mmol) in EtOH(15 mL) were added NH₂OH.HCl (769 mg, 11.1 mmol) and TEA (1.12 g, 11.1mmol). The mixture was stirred at 70° C. for 4 h. The mixture wasconcentrated under reduced pressure to give a residue. The residue wasdiluted with EtOAc (30 mL). The organic layer was washed with H₂O (30mL). The aqueous phase was extracted with EtOAc (30 mL). The combinedorganic layers were dried over anhydrous sodium sulfate, filtered, andconcentrated to give N-hydroxy-5-methoxypicolinimidamide (900 mg, 5.38mmol, 97% yield, 99% purity).

3-(5-Methoxypyridin-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole

To a solution of N-hydroxy-5-methoxypicolinimidamide (900 mg, 5.38 mmol)in toluene (30 mL) was added trichloroacetic anhydride (3.32 g, 10.8mmol). The mixture was stirred at 110° C. for 3 h. The mixture wasconcentrated under reduce pressure to give a residue. The residue wasdiluted with EtOAc (50 mL). The organic layer was washed with sodiumbicarbonate (20 mL). The aqueous phase was extracted with EtOAc. Thecombined organic layers were wash with brine, dried over anhydroussodium sulfate, filtered, and concentrated to give a residue. Theresidue was purified by silica gel chromatography to give3-(5-methoxypyridin-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (1.50 g,5.01 mmol, 93% yield, 98% purity).

3-(5-Methoxypyridin-2-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-oxadiazol-5-amine

To a solution of 4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-amine (396mg, 2.04 mmol) in THF (15 mL) was added NaH (73 mg, 3.06 mmol) slowly at0° C. The mixture was stirred at 25° C. for 0.5 h under N₂. Then asolution of3-(5-methoxypyridin-2-yl)-5-(trichloromethyl)-1,2,4-oxadiazole (600 mg,2.04 mmol) in THF (5 mL) was added to the reaction mixture. The reactionmixture was stirred at 25° C. for 12 h under N₂. The product wasisolated and purified via standard methods to give3-(5-methoxypyridin-2-yl)-N-(4-((tetrahydro-2H-pyran-4-yl)oxy)pyridin-2-yl)-1,2,4-oxadiazol-5-amine(74.27 mg, 0.198 mmol, 10% yield, 98.4% purity). LCMS (ESI): m/z 370.2[M+1]⁺.

Example 30:N,N-dimethyl-6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-oxadiazol-3-yl)nicotinamide

6-cyano-N,N-dimethylnicotinamide

To a solution of 6-cyanonicotinic acid (400 mg, 2.70 mmol),N-methylmethanamine (264 mg, 3.24 mmol, HCl) and DIPEA (1.05 g, 8.10mmol) in DCM (20 mL) was added HATU (1.23 g, 3.24 mmol) at 0° C. Themixture was stirred at 25° C. for 3 h. The mixture was concentrated. Theresidue was purified by prep-TLC to give6-cyano-N,N-dimethylnicotinamide (400 mg, crude). ¹H NMR (400 MHz,CDCl3) δ 8.76 (dd, J1=2.0, J2=0.8 Hz, 1H), 7.91 (dd, J1=8.0, J2=2.0 Hz,1H), 7.77 (dd, J1=8.0, J2=0.8 Hz, 1H), 3.15 (s, 3H), 3.01 (s, 3H).

6-(N-Hydroxycarbamimidoyl)-N,N-dimethylnicotinamide

To a solution of 6-cyano-N,N-dimethylnicotinamide (600 mg, 3.42 mmol)and TEA (692 mg, 6.84 mmol) in EtOH (20 mL) was added NH₂OH.HCl (475 mg,6.84 mmol). The mixture was stirred at 80° C. for 16 h. The mixture wasconcentrated. The residue was diluted with 150 mL of EtOAc and 50 mL ofH₂O. The organic phase was separated and dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum to give6-(N-hydroxycarbamimidoyl)-N,N-dimethylnicotinamide (650 mg, crude).

N,N-Dimethyl-6-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide

To a solution of 6-(N-hydroxycarbamimidoyl)-N,N-dimethylnicotinamide(650 mg, 3.12 mmol) in toluene (30 mL) was added trichloroaceticanhydride (1.93 g, 6.24 mmol). The mixture was stirred at 110° C. for 16h. The mixture was concentrated under vacuum. The residue was purifiedby silica gel to giveN,N-dimethyl-6-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide(700 mg, 2.04 mmol, 65% yield, 97.6% purity).

N,N-Dimethyl-6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-oxadiazol-3-yl)nicotinamide

To a solution of 3-methylpyridin-2-amine (116 mg, 1.07 mmol) in THF (10mL) was added NaH (54 mg, 1.34 mmol, 60% purity). The mixture wasstirred at 25° C. for 0.5 h. ThenN,N-dimethyl-6-(5-(trichloromethyl)-1,2,4-oxadiazol-3-yl)nicotinamide(300 mg, 0.894 mmol) in THE (5 mL) was added. The mixture was stirred at25° C. for 2.5 h. The product was isolated and purified via standardmethods to giveN,N-dimethyl-6-(5-((3-methylpyridin-2-yl)amino)-1,2,4-oxadiazol-3-yl)nicotinamide(53.80 mg, 0.166 mmol, 19% yield, 99.9% purity). LCMS (ESI): m/z 325.2[M+1]⁺.

Example 31:3-(5-Isopropoxypyrazin-2-yl)-N-(3-methylpyridine-2-yl)-1,2,4-thiadiazol-5-amine

5-Isopropoxypyrazine-2-carbonitrile

To a mixture of propan-2-ol (3.23 g, 53.75 mmol) in DMF (40 mL) wasadded sodium hydrogen (2.15 g, 53.75 mmol, 60% purity) in portions at 0°C. under nitrogen. The mixture was stirred at 25° C. for 30 min, then5-chloropyrazine-2-carbonitrile (5 g, 35.83 mmol) was added and themixture was stirred at 25° C. for 3 h. The mixture was poured into H₂O(100 mL) and extracted with EtOAc. The combined organic phases werewashed with brine, dried over sodium sulfate, filtered and concentratedat reduced pressure to give a residue. The residue was purified bysilica gel chromatography to give 5-isopropoxypyrazine-2-carbonitrile(3.8 g, 23.29 mmol, 64.99% yield).

5-Isopropoxypyrazine-2-carboximidamide

Sodium (141 mg, 6.13 mmol) was added into MeOH (20 mL). To the mixture5-isopropoxypyrazine-2-carbonitrile (2 g, 12.26 mmol) was added and themixture was stirred at 25° C. for 2 h. NH₄Cl (983 mg, 18.38 mmol) wasadded and the mixture was stirred at 70° C. for 1.5 h. The hot mixturewas filtered and the filtrate was concentrated to give a residue. Theresidue was triturated with Petroleum ether:EtOAc (10:1, 50 mL) to givethe crude product as hydrochloride salt. The product was isolated andpurified by standard methods to give5-isopropoxypyrazine-2-carboxamidine (1.8 g, 9.99 mmol, 81.49% yield).LCMS (ESI): m/z 329.1 [M+1]⁺.

Example32:3-(5-Cyclopropoxy-3-(trifluoromethyl)pyridin-2-yl)-n-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

5-Chloro-3-(trifluoromethyl)picolinonitrile

To a mixture of 5-amino-3-(trifluoromethyl)picolinonitrile (1.8 g, 9.62mmol) and cuprous chloride (1.43 g, 14.4 mmol) in hydrochloric acid (30mL) was stirred at 0° C. for 0.5 h. Then a solution of sodium nitrite(730.0 mg, 10.6 mmol) in H₂O (30 mL) was added drop wise to the mixtureand the mixture was stirred at 0° C. for another 0.5 h. The mixture wasextracted with EtOAc. The combined organic phases were dried withanhydrous sodium sulphate, filtered and concentrated to give5-chloro-3-(trifluoromethyl)picolinonitrile (1.9 g, 8.55 mmol, 88.93%yield).

5-Cyclopropoxy-3-(trifluoromethyl)picolinonitrile

To a mixture of NaH (376.0 mg, 9.41 mmol, 60% purity) in DMF (30 mL) wasadded a solution of cyclopropanol (497.0 mg, 8.55 mmol) in DMF (5 mL) at−20° C. under N₂. The reaction mixture was stirred at −20° C. for 0.5 hand then a solution of 5-chloro-3-(trifluoromethyl)picolinonitrile (1.9g, 8.55 mmol) in DMF (5 mL) was added to the mixture. The mixture wasthen stirred at this temperature for another 20 min. The mixture wasquenched by cold saturated NH₄Cl solution (150 mL). The aqueous phasewas extracted with EtOAc. The combined organic phases were then washedwith saturated brine, dried with anhydrous sodium sulfate, filtered andconcentrated to give crude yellow oil which was purified by silica gelchromatography to give 5-cyclopropoxy-3-(trifluoromethyl)picolinonitrile(1.85 g, 6.41 mmol, 74.87% yield).

5-Cyclopropoxy-3-(trifluoromethyl)picolinimidamide

To a mixture of 5-cyclopropoxy-3-(trifluoromethyl)picolinonitrile (840mg, 3.68 mmol) in MeOH (30 mL) was added sodium methoxide (99.44 mg,1.84 mmol), the mixture was stirred at 25° C. for 3 h. NH₄Cl (295.0 mg,5.52 mmol) was then added to the mixture and the mixture was thenstirred at 75° C. for another 2 h. and was concentrated to remove MeOHand then dissolved with EtOH (5 mL). The mixture was heated at 70° C.for 0.5 h and then filtered. The filtrate was concentrated to give asolid which was triturated by EtOAc (5 mL) to give 500 mg product. Thesolid was combined with another batch and then purified by Cis reversecolumn (0%-100% ACN in H₂O (0.5% HCl) to give a solution of pure productin ACN and H₂O). OH-type resin was added to the mixture and the mixturewas filtered and lyophilized to give5-cyclopropoxy-3-(trifluoromethyl)picolinimidamide (240 mg, 919.0 μmol,24.97% yield).

5-Cyclopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)-3-(trifluoromethyl)picolinimidamide

To a mixture of 5-cyclopropoxy-3-(trifluoromethyl)picolinimidamide (550mg, 2.24 mmol) and TEA (454.0 mg, 4.49 mmol) in DCM (1 mL) was added2-isothiocyanato-3-methylpyridine (337.0 mg, 2.24 mmol). The mixture wasthen stirred at 25° C. for 1 h. and was concentrated to give a solid.The solid was triturated with MTBE (20 mL) to give5-cyclopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)-3-(trifluoromethyl)picolinimidamide(550 mg, 1.26 mmol, 56.29% yield).

3-(5-Cyclopropoxy-3-(trifluoromethyl)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of5-cyclopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)-3-(trifluoromethyl)picolinimidamide(500 mg, 1.26 mmol) in EtOH (20 mL) and DCM (20 mL) was added hydrogenperoxide (287.0 mg, 2.53 mmol, 30% purity) and iodine (64.2 mg, 253.0μmol). The reaction mixture was then stirred at 25° C. for 2 h and wasconcentrated to give a solid which was triturated with methyl tertiarybutyl ether (10 mL) and EtOAc (1 mL) to give a solid. The solid wastriturated with ACN (2 mL) to give3-(5-cyclopropoxy-3-(trifluoromethyl)pyridin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine(167.66 mg, 422.28 μmol, 33.39% yield). LCMS (ESI): m/z 394.0 [M+1]⁺.

5-Isopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)pyrazine-2-carboximidamide

To a mixture of 5-isopropoxypyrazine-2-carboxamidine (240 mg, 1.33 mmol)and 2-isothiocyanato-3-methylpyridine (0.3 g, 1.88 mmol) in DCM (10 mL)and acetone (10 mL) was added TEA (404 mg, 4.00 mmol). The mixture wasstirred at 25° C. for 5 h under nitrogen and was concentrated at reducedpressure to give a residue. Saturated sodium carbonate was added intothe residue and the mixture was extracted with EtOAc. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedat reduced pressure to give5-isopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)pyrazine-2-carboximidamide(0.5 g, crude).

3-(5-Isopropoxypyrazin-2-yl)-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of5-isopropoxy-N-((3-methylpyridin-2-yl)carbamothioyl)pyrazine-2-carboximidamide(0.5 g) and hydrogen peroxide (343 mg, 3.03 mmol, 30% purity) in EtOH(20 mL) was added iodine (7.68 mg, 0.03 mmol). The mixture was stirredat 25° C. for 1 h. The mixture was quenched with saturated sodiumsulfite (5 mL) at 0° C. Then the mixture was diluted with H₂O andextracted with EtOAc. The combined organic phases were washed withbrine, dried over sodium sulfate, filtered and concentrated at reducedpressure to give a residue. The product was isolated and purified bystandard methods to give3-(5-isopropoxypyrazin-2-yl)-N-(3-methyl-2-pyridyl)-1,2,4-thiadiazol-5-amine(160.14 mg, 0.447 mmol). LCMS (ESI): m/z 329.1 [M+1]⁺.

Example 33:N³,N³-Dimethyl-N²-(3-(5-((1-methylazetidin-3-yl)sulfonyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine

Tert-Butyl 3-(acetylthio)azetidine-1-carboxylate

To a mixture of tert-butyl 3-iodoazetidine-1-carboxylate (20 g, 70.64mmol) in DMF (400 mL) was added potassium ethanethioate (16.14 g, 141.29mmol). The mixture was stirred at 70° C. for 16 h under nitrogen. Themixture was poured into H₂O and the resulting mixture was extracted withEtOAc. The combined organic phases were washed with brine, dried oversodium sulfate, filtered and concentrated at reduced pressure to give aresidue. The residue was purified by silica gel chromatography to givetert-butyl 3-acetylsulfanylazetidine-1-carboxylate (12 g, 51.88 mmol,73.44% yield).

Tert-Butyl 3-mercaptoazetidine-1-carboxylate

Sodium (2.39 g, 103.76 mmol) was added into MeOH (50 mL) in portions andthe mixture was stirred at 25° C. for 30 min. Then this mixture wasadded into tert-butyl 3-acetylsulfanylazetidine-1-carboxylate (12 g,51.88 mmol) which was dissolved in MeOH (50 mL) slowly at 0° C. Themixture was stirred at 25° C. for 4 h and was concentrated at reducedpressure to give a residue. The residue was diluted with H₂O andadjusted pH to about 7 with 6 M HCl acid. The resulting mixture wasextracted with DCM. The combined organic phases were washed with brine,dried over sodium sulfate, filtered and concentrated at reduced pressureto give a residue. The residue was purified by silica gel chromatographyto give tert-butyl 3-mercaptoazetidine-1-carboxylate (8 g, 42.27 mmol,81.47% yield).

Tert-Butyl 3-((6-cyanopyridin-3-yl)thio)azetidine-1-carboxylate

To a mixture of tert-butyl 3-mercaptoazetidine-1-carboxylate (8 g, 42.27mmol) in DMF (50 mL) was added NaH (2.03 g, 50.72 mmol, 60% purity) inportions at 0° C. under nitrogen. The mixture was stirred at 25° C. for30 min, then 5-fluoropyridine-2-carbonitrile (5.16 g, 42.27 mmol) in DMF(10 mL) was added slowly and the mixture was stirred at 25° C. for 2 h.The mixture was diluted with H₂O (500 mL) and the mixture was extractedwith EtOAc. The combined organic phases were washed with brine, driedover sodium sulfate, filtered and concentrated at reduced pressure togive a residue. The residue was purified by silica gel chromatography togive tert-butyl 3-((6-cyanopyridin-3-yl)thio)azetidine-1-carboxylate (7g, crude).

Tert-Butyl 3-((6-cyanopyridin-3-yl)sulfonyl)azetidine-1-carboxylate

To a mixture of tert-butyl3-[(6-cyano-3-pyridyl)sulfanyl]azetidine-1-carboxylate (3 g) in DCM (30mL) was added m-chlorine perbenzoic acid (5.55 g, 25.73 mmol, 80%purity) which was dissolved with DCM (50 mL) slowly at 25° C. undernitrogen. The mixture was stirred at 25° C. for 2 h. The mixture wasquenched with saturated sodium sulfite (30 mL). The mixture wasseparated and the organic phase was washed with saturated sodiumcarbonate, brine, dried over sodium sulfate, filtered and concentratedat reduced pressure to give a residue. The residue was purified bysilica gel chromatography to give tert-butyl3-((6-cyanopyridin-3-yl)sulfonyl) azetidine-1-carboxylate (2.8 g, 8.66mmol).

5-(Azetidin-3-ylsulfonyl)picolinonitrile

To a mixture of tert-butyl 3-((6-cyanopyridin-3-yl)sulfonyl)azetidine-1-carboxylate (2.8 g, 8.66 mmol) in DCM (30 mL) was addedtrifluoroacetic acid (9.24 g, 81.04 mmol) slowly at 0° C. undernitrogen. The mixture was stirred at 0° C. for 1 h. The reaction mixturewas purified by silica gel chromatography; TLC to give5-(azetidin-3-ylsulfonyl)picolinonitrile trifluoroacetic acid (2.3 g,6.82 mmol, 78.76% yield).

5-((1-Methylazetidin-3-yl)sulfonyl)picolinonitrile

To a mixture of 5-(azetidin-3-ylsulfonyl)picolinonitrile trifluroaceticacid (2.3 g, 6.82 mmol) in MeOH (10 mL) was added TEA (828.06 mg, 8.18mmol). The mixture was stirred at 25° C. for 30 min, then formaldehyde(5.53 g, 68.19 mmol) and acetic acid (122.86 mg, 2.05 mmol) were addedand the mixture was stirred at 25° C. for 2 h. Then sodiumcyanoborohydride (1.29 g, 20.46 mmol) was added in portions at 0° C. andthe mixture was stirred at 25° C. for 14 h. The mixture was adjusted pHto about 7 with saturated sodium bicarbonate. The resulting mixture wasconcentrated at reduced pressure to give a residue which was dilutedwith saturated sodium carbonate and extracted with DCM. The combinedorganic phases were dried over sodium sulfate, filtered and concentratedat reduced pressure to give a residue. The residue was purified bysilica gel chromatography to give5-((1-methylazetidin-3-yl)sulfonyl)picolinonitrile (0.6 g).

5-((1-Methylazetidin-3-yl)sulfonyl)picolinonitrile

Sodium (29.07 mg, 1.26 mmol) was added into MeOH (10 mL) and thismixture was stirred at 25° C. for 0.5 h.5-((1-Methylazetidin-3-yl)sulfonyl)picolinonitrile (0.6 g, 2.53 mmol)was added into the mixture and the mixture was stirred at 25° C. for 2h. NH₄Cl (202.89 mg, 3.79 mmol) was added and the mixture was stirred at70° C. for 1 hour. The hot mixture was filtered and the filtrate wasconcentrated at reduced pressure to give5-(1-methylazetidin-3-yl)sulfonylpyridine-2-carboxamidine hydrochloride(0.9 g, crude).

N-((3-(Dimethylamino)pyridin-2-yl)carbamothioyl)-5-((1-methylazetidin-3-yl)sulfonyl)picolinimidamide

To a mixture of5-(1-methylazetidin-3-yl)sulfonylpyridine-2-carboxamidine hydrochloride(0.8 g) and 2-isothiocyanato-N,N-dimethylpyridin-3-amine (563.86 mg,3.15 mmol) in DCM (15 mL) and acetone (15 mL) was added TEA (954.97 mg,9.44 mmol). The mixture was stirred at 25° C. for 2 h under nitrogen.The mixture (combined with another batch) was concentrated at reducedpressure to give a residue. The residue was diluted with saturatedsodium bicarbonate and the resulting mixture was extracted with EtOAc.The combined organic phases were washed with brine, dried over sodiumsulfate, filtered and concentrated at reduced pressure to giveN-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)-5-((1-methylazetidin-3-yl)sulfonyl)picolinimidamide (1 g, crude).

N³,N³-Dimethyl-N²-(3-(5-((1-methylazetidin-3-yl)sulfonyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine

To a mixture ofN-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)-5-((1-methylazetidin-3-yl)sulfonyl)picolinimidamide (1 g, crude) and hydrogen peroxide (523 mg,4.61 mmol) in EtOH (20 mL) was added iodine (117 mg, 0.461 mmol) inportions. The mixture was stirred at 25° C. for 1 h. The mixture wasquenched with saturated sodium sulfite (5 mL) at 0° C. and the resultingmixture was concentrated at reduced pressure to give a residue. Theproduct was isolated and purified by standard methods to giveN³,N³-dimethyl-N²-(3-(5-((1-methylazetidin-3-yl)sulfonyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamineformic acid (290.8 mg, 0.597 mmol, 98% purity). LCMS (ESI): m/z 432.1[M+1]⁺

Example 34:N-(3,3-difluorocyclobutyl)-6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinamide

Methyl 6-amino-5-bromonicotinate

To a mixture of methyl 6-aminonicotinate (15 g, 98.59 mmol, 1 eq) in TH(300 mL) was added N-bromobutanimide (18.42 g, 103.52 mmol) in portionsat 0° C. The mixture was stirred at 25° C. for 2 h. The reaction mixturewas concentrated under vacuum. The residue was purified by silica gelchromatography to give methyl 6-amino-5-bromonicotinate (19 g, 79.77mmol, 80.91% yield).

Methyl 6-amino-5-(prop-1-en-2-yl)nicotinate

To a mixture of methyl 6-amino-5-bromonicotinate (10 g, 43.28 mmol) andpotassium; trifluoro(isopropenyl)boranuide (9.61 g, 64.92 mmol) indioxane (150 mL) and H₂O (30 mL) were added[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.58 g,2.16 mmol) and sodium carbonate (9.17 g, 86.56 mmol) under nitrogen. Themixture was stirred at 80° C. for 12 h under nitrogen. The reactionmixture was concentrated under vacuum and the residue was diluted withH₂O. The aqueous phase was extracted with EtOAc and the combined organicphases were dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography to give methyl 6-amino-5-(prop-1-en-2-yl)nicotinate (6.3g, 30.48 mmol, 70.43% yield).

Methyl 6-amino-5-isopropylnicotinate

To a mixture of methyl 6-amino-5-(prop-1-en-2-yl)nicotinate (6.3 g,30.48 mmol) in MeOH (90 mL) were added Pd/C (0.3 g, 10%) and hydroxidePd/C (0.3 g, 20%). The mixture was stirred at 20° C. for 3 h underhydrogen (15 psi). The mixture was filtered and the filtrate wasconcentrated under vacuum to give methyl 6-amino-5-isopropylnicotinate(3.3 g, 15.80 mmol, 51.84% yield).

Methyl 5-isopropyl-6-isothiocyanatonicotinate

To a mixture of thiophosgene (1.98 g, 17.24 mmol, 1.32 mL) in DCM (40mL) was added a solution of methyl 6-amino-5-isopropylnicotinate (1.8 g,8.62 mmol) in DCM (20 mL) dropwise at 0° C. The mixture was stirred at0° C. for 1 h. The mixture was quenched with saturated sodiumbicarbonate. The organic phase was dried with anhydrous sodium sulfate,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography to give methyl 5-isopropyl-6-isothiocyanatonicotinate(1.8 g, 7.62 mmol, 88.39% yield).

Methyl-6-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)-5-isopropylnicotinate

To a mixture of methyl 5-isopropyl-6-isothiocyanatonicotinate (0.9 g,3.81 mmol) and 5-isopropoxypicolinimidamide (682.62 mg, 3.81 mmol) inDCM (20 mL) and acetone (20 mL) was added TEA (1.93 g, 19.04 mmol). Themixture was stirred at 20° C. for 3 h under nitrogen and wasconcentrated under vacuum to give methyl6-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)-5-isopropylnicotinate(1.6 g, crude).

Methyl-6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinate

To a mixture of methyl6-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)-5-isopropylnicotinate(1.6 g, crude) in EtOH (30 mL) were added iodine (195.47 mg, 0.770 mmol)and hydrogen peroxide (873.20 mg, 7.70 mmol, 30% purity) at 0° C. Themixture was stirred at 20° C. for 1 h. The mixture was quenched withsaturated sodium sulfite (20 mL) at 0° C. and concentrated. The residuewas diluted with H₂O and extracted with EtOAc. The combined organicphases were dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography togivemethyl-6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinate(1.2 g, 2.41 mmol, 62.55% yield).

6-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinicAcid

To a mixture of methyl6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinate(1.2 g, 2.41 mmol) in MeOH (20 mL) was added a solution of lithiumhydroxide (1.01 g, 24.09 mmol) in H₂O (10 mL). The mixture was stirredat 20° C. for 22 h and 50° C. for 12 h. and was concentrated undervacuum. The aqueous phase was adjusted to pH of 5 with 6 N HCl. Theresulting suspension was filtered and the filter cake was dried bylyophilization to give6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinicacid (0.9 g, 2.25 mmol, 93.53% yield).

N-(3,3-difluorocyclobutyl)-6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinamide

To a mixture of6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinicacid (500 mg, 1.25 mmol) and 3,3-difluorocyclobutanamine (215.63 mg,1.50 mmol, HCl) in DMF (10 mL) were added HATU (713.88 mg, 1.88 mmol)and DIPEA (485.31 mg, 3.76 mmol). The mixture was stirred at 20° C. for4 h. The mixture was diluted with 100 mL of EtOAc. The organic phase waswashed with brine, dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The product was isolated and purified bystandard methods to giveN-(3,3-difluorocyclobutyl)-6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-isopropylnicotinamide(228.0 mg, 0.467 mmol, 37.28% yield). LCMS (ESI): m/z 489.3 [M+1]⁺.

Example 35:N²-(3-(5-Isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine

Methyl 5-chloro-4-(trifluoromethyl)picolinate

To a mixture of 2,5-dichloro-4-(trifluoromethyl)pyridine (5 g, 23.15mmol) in MeOH (100 mL) were addedbis(diphenylphosphino)ferrocene]dichloropalladium (846.93 mg, 1.16 mmol)and TEA (7.03 g, 69.45 mmol, 9.67 mL) under nitrogen. The mixture wasstirred at 60° C. for 3 h under carbon monoxide (50 psi). The mixturewas filtered and the filtrate was concentrated. The residue was purifiedby silica gel chromatography to give methyl5-chloro-4-(trifluoromethyl)picolinate (4.5 g, 18.78 mmol, 81.14%yield).

5-Chloro-4-(trifluoromethyl)picolinamide

To a mixture of methyl 5-chloro-4-(trifluoromethyl)picolinate (4.5 g,17.78 mmol) in MeOH (100 mL) was added ammonia/MeOH (29 M, 45.34 mL) at0° C. The mixture was stirred at 15° C. for 16 h. and was concentratedto give 5-chloro-4-(trifluoromethyl)picolinamide (4 g, 17.81 mmol,94.83% yield).

5-Chloro-4-(trifluoromethyl)picolinonitrile

To a mixture of 5-chloro-4-(trifluoromethyl)picolinamide (4 g, 17.81mmol) and TEA (9.01 g, 148.06 mmol) in DCM (200 mL) was addedtrifluoroacetic anhydride (18.66 g, 88.84 mmol) at 0° C. The mixture wasstirred at 25° C. for 3 h. The mixture was poured into cold H₂O. Theorganic phase was separated and the aqueous phase was extracted withDCM. The combined organic phases were concentrated under vacuum. Theresidue was purified by silica gel chromatography to give5-chloro-4-(trifluoromethyl)picolinonitrile (3.6 g, 17.43 mmol, 97.85%yield).

5-Isopropoxy-4-(trifluoromethyl)picolinonitrile

To a mixture of NaH (1.74 g, 43.57 mmol, 60% purity) in DMF (40 mL) wasadded propan-2-ol (2.09 g, 34.86 mmol) at −20° C. under nitrogen. Themixture was stirred at −10° C. for 0.5 h under nitrogen. Then5-chloro-4-(trifluoromethyl)picolinonitrile (3.6 g, 17.43 mmol) in DMF(10 mL) was added into the above mixture at −20° C. The mixture wasstirred at −20° C. for 1 h. The mixture was poured into cold saturatedNH₄Cl slowly. The mixture was diluted with 300 mL of EtOAc. The organicphase was washed with brine. The organic phase was dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by silica gel chromatography to give5-isopropoxy-4-(trifluoromethyl)picolinonitrile (3 g, 12.38 mmol, 71.04%yield).

5-Isopropoxy-4-(trifluoromethyl)picolinimidamide hydrochloride

Sodium (25 mg, 1.09 mmol) was added into MeOH (10 mL). To the mixturewas added 5-isopropoxy-4-(trifluoromethyl)picolinonitrile (0.5 g, 2.17mmol). The mixture was stirred at 15° C. for 3 h. NH₄Cl (174.28 mg, 3.26mmol) was added. The mixture was stirred at 70° C. for 2 h. The hotmixture was filtered and the filtrate was concentrated to give aresidue. The residue was triturated with petroleum ether:EtOAc (2:1, 15mL) to give 5-isopropoxy-4-(trifluoromethyl)picolinimidamidehydrochloride (0.6 g, crude).

N-((3-(Dimethylamino)pyridin-2-yl)carbamothioyl)-5-isopropoxy-4-(trifluoromethyl)picolinimidamide

To a mixture of 2-isothiocyanato-N,N-dimethylpyridin-3-amine (0.38 g,2.12 mmol) and 5-isopropoxy-4-(trifluoromethyl)picolinimidamidehydrochloride (601 mg, crude) in DCM (15 mL) and acetone (15 mL) wasadded TEA (2.15 g, 21.20 mmol, 2.95 mL). The mixture was stirred at 15°C. for 16 h under nitrogen and was concentrated and the residue waspoured into H₂O. The aqueous phase was extracted with EtOAc. Thecombined organic phases were dried over anhydrous sodium sulfate,filtered and concentrated under vacuum to giveN-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)-5-isopropoxy-4-(trifluoromethyl)picolinimidamide (1 g,1.34 mmol, 63.05% yield).

N²-(3-(5-Isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine

To a mixture ofN-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)-5-isopropoxy-4-trifluoromethyl)picolinimidamide(1 g, 1.34 mmol, 57% purity) in EtOH (20 mL) were added iodine (67.85mg, 0.267 mmol) and hydrogen peroxide (454.57 mg, 4.01 mmol, 30% purity)at 0° C. The mixture was stirred at 15° C. for 0.5 h and then quenchedwith saturated sodium sulfite. The mixture was concentrated to removethe organic solvent. The product was isolated and purified by standardmethods to giveN²-(3-(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diamine(431.76 mg, 1.01 mmol, 75.93% yield). LCMS (ESI) m/z 425.1 [m+1]⁺.

Example 36:N-(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide

tert-Butyl(2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-isothiocyanatopyridin-3-yl)(methyl)carbamate (0.4 g, 1.42 mmol) and5-isopropoxypicolinimidamide (254 mg, 1.42 mmol) in DCM (10 mL) andacetone (10 mL) was added TEA (430 mg, 4.25 mmol). The mixture wasstirred at 15° C. for 2 h and was concentrated at reduced pressure togive a residue. The residue was diluted with saturated sodiumbicarbonate and the resulting mixture was extracted with EtOAc. Thecombined organic phases were washed with brine, dried over sodiumsulfate, filtered and concentrated at reduced pressure to givetert-butyl(2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.7 g, crude).

tert-Butyl(2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridine-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.7 g, crude) and hydrogen peroxide (357 mg, 3.15 mmol, 30% purity) inEtOH (10 mL) was added iodine (79.93 mg, 0.315 mmol) in portions. Themixture was stirred at 15° C. for 0.5 h. The mixture was quenched withsaturated sodium sulfite at 0° C. and the resulting mixture wasconcentrated at reduced pressure to give a residue. The mixture wasdiluted with H2O and the resulting mixture was extracted with DCM. Thecombined organic phases were washed with brine, dried over sodiumsulfate, filtered and concentrated at reduced pressure to give aresidue. The residue was purified by silica gel chromatography to givetert-butyl(2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate(0.4 g, 0.777 mmol, 49.37% yield, 86% purity).

N2-(3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N3-methylpyridine-2,3-diaminehydrochloride

To a mixture of tert-butyl(2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate(0.4 g, 0.777 mmol, 86% purity) in EtOAc (15 mL) was addedhydrochloride/EtOAc (4 M, 19.43 mL) at 0° C. The mixture was stirred at20° C. for 3 h. The mixture was concentrated to giveN2-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N3-methylpyridine-2,3-diaminehydrochloride (0.3 g, 0.673 mmol, 86.58% yield, 85% purity).

N-(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide.To a mixture ofN2-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N3-methylpyridine-2,3-diaminehydrochloride (200 mg, 0.449 mmol) in ACN (20 mL) were added TEA (454mg, 4.49 mmol) and Ac₂O (59.55 mg, 0.583 mmol). The mixture was stirredat 30° C. for 16 h and was concentrated. The product was isolated andpurified by standard methods to giveN-(2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide(183.19 mg, 0.468 mmol, 69.59% yield, 98.3% purity). LCMS (ESI) m/z385.2 [M+1]⁺.

Example 37:2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

Methyl 2-isothiocyanatonicotinate

To a mixture of thiophosgene (11.34 g, 98.59 mmol, 7.56 mL) in DCM (50mL) was added methyl 2-aminonicotinate (5 g, 32.86 mmol) which wasdissolved with DCM (50 mL) slowly at 0° C. The mixture was stirred at 0°C. for 2 h. The mixture was quenched with saturated sodium bicarbonateslowly at 0° C. and the resulting mixture was separated. The organicphase was dried over sodium sulfate, filtered and concentrated atreduced pressure to give a residue. The residue was purified by silicagel chromatography; TLC to give methyl 2-isothiocyanatonicotinate (4.5g, 23.17 mmol, 70.51% yield).

Methyl 2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)nicotinate

To the mixture methyl 2-isothiocyanatonicotinate (1 g, 5.15 mmol) and5-isopropoxypicolinimidamide (922.81 mg, 5.15 mmol) in DCM (10 mL) andacetone (10 mL) was added TEA (1.56 g, 15.45 mmol, 2.15 mL). The mixturewas stirred at 20° C. for 4 h. The reaction was concentrated to give aresidue. The residue was diluted with H₂O and extracted EtOAc. Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated under reduced pressure to give methyl2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)nicotinate (1.88g, crude).

Methyl2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinate

To the mixture of methyl2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)-thioureido)nicotinate (1.88g, crude) and hydrogen peroxide (1.54 g, 13.58 mmol, 1.31 mL, 30%purity) in EtOH (50 mL) was added iodine (230 mg, 0.91 mmol) at 0° C.The mixture was stirred at 20° C. for 1.5 h. The reaction mixture wasquenched with saturated sodium sulfite at 0° C. and the residue wasdiluted with H₂O and extracted with DCM. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate, filteredand concentrated under reduced pressure to give methyl2-((3-(5-isopropoxy-pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinate(0.6 g, crude).

2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

To a mixture of methyl2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinate(0.6 g, crude) in MeOH (15 mL) was added ammonia/MeOH (24.5 M, 15 mL) at0° C. The mixture was stirred at 15° C. for 16 h. The reaction wasstirred at 50° C. for an additional 2 h. To the mixture was addedammonia/MeOH (20 M, 15 mL). The mixture was stirred at 50° C. foranother 2 h and was concentrated. The product was isolated and purifiedby standard methods to give2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide(333.04 mg, 0.89 mmol, 54.95% yield, 95% purity). LCMS (ESI): m/z 357.3[M+1]⁺.

Example38:2-((3-(5-Isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylnicotinamide

Methyl 5-chloro-4-(trifluoromethyl)picolinate

To a mixture of 2,5-dichloro-4-(trifluoromethyl)pyridine (5 g, 23.15mmol) in MeOH (100 mL) were addedBis(diphenylphosphino)ferrocene]dichloropalladium (846.93 mg, 1.16mmol), BINAP (360.36 mg, 0.579 mmol) and TEA (7.03 g, 69.45 mmol, 9.67mL) under nitrogen. The mixture was stirred at 60° C. for 3 h undercarbon monoxide (50 psi). The mixture was filtered and the filtrate wasconcentrated. The residue was purified by silica gel chromatography togive methyl 5-chloro-4-(trifluoromethyl)picolinate (5.0 g, 20.87 mmol,90.15% yield).

5-Chloro-4-(trifluoromethyl)picolinamide

To a mixture of methyl 5-chloro-4-(trifluoromethyl)picolinate (5.0 g,20.87 mmol) in MeOH (50 mL) was added ammonia/MeOH (10 M, 62.61 mL) at0° C. The mixture was stirred at 25° C. for 16 h. and was concentratedto give 5-chloro-4-(trifluoromethyl)picolinamide (4.5 g, 20.04 mmol,96.02% yield).

5-Chloro-4-(trifluoromethyl)picolinonitrile

To a mixture of 5-chloro-4-(trifluoromethyl)picolinamide (4.5 g, 20.04mmol) and TEA (10.14 g, 100.19 mmol) in DCM (100 mL) was addedtrifluoroacetic anhydride (12.63 g, 60.12 mmol) at 0° C. The mixture wasstirred at 25° C. for 2 h. The mixture was poured into cold H₂O. Theorganic phase was separated and the aqueous phase was extracted withDCM. The combined organic phases were concentrated under vacuum. Theresidue was purified by silica gel chromatography to give5-chloro-4-(trifluoromethyl)picolinonitrile (3.8 g, 18.4 mmol, 91.81%yield).

5-Isopropoxy-4-(Trifluoromethyl)picolinonitrile

To a mixture of NaH (1.84 g, 45.99 mmol, 60% purity) in DMF (40 mL) wasadded propan-2-ol (2.21 g, 36.79 mmol) at −20° C. under nitrogen. Themixture was stirred at −10° C. for 0.5 h under nitrogen. Then5-chloro-4-(trifluoromethyl)picolinonitrile (3.8 g, 18.4 mmol) in DMF(10 mL) was added into the above mixture at −20° C. The mixture wasstirred at −20° C. for 1 h. The mixture was poured into cold saturatedNH₄Cl slowly. The mixture was diluted with EtOAc. The organic phase waswashed with brine and dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography to give crude product. The crude product was purified byreverse MPLC (ACN/H₂O, formic acid) to give5-isopropoxy-4-(trifluoromethyl)picolinonitrile (0.4 g, 1.74 mmol, 9.46%yield). The residue was purified by prep-HPLC (column: PhenomenexSynergi Max-RP 250*50 mm*10 μm; mobile phase: [H₂O (0.225% FA)-ACN]; B%: 30%-60%, 32 MIN, 60% min) to give5-isopropoxy-4-(trifluoromethyl)picolinonitrile (0.8 g, 3.48 mmol).

5-Isopropoxy-4-(trifluoromethyl)picolinimidamide Hydrochloride

Sodium (20 mg, 0.869 mmol) was added into MeOH (5 mL). To the mixturewas added 5-isopropoxy-4-(trifluoromethyl)picolinonitrile (0.4 g, 1.74mmol). The mixture was stirred at 25° C. for 2 h. NH₄Cl (139 mg, 2.61mmol) was added and the mixture was stirred at 70° C. for 2 h. The hotmixture was filtered and the filtrate was concentrated to give aresidue. The residue was triturated with petroleum ether:EtOAc (2:1, 30mL) to give 5-isopropoxy-4-(trifluoromethyl)picolinimidamidehydrochloride (0.5 g, 1.73 mmol, 99.4% yield).

Methyl-2-(3-(imino(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)methyl)thioureido)nicotinate

To a mixture of 5-isopropoxy-4-(trifluoromethyl)picolinimidamidehydrochloride (0.5 g, 1.73 mmol) and methyl 2-isothiocyanatonicotinate(436 mg, 2.25 mmol) in DCM (30 mL) and acetone (30 mL) was added TEA(873.93 mg, 8.64 mmol). The mixture was stirred at 25° C. for 18 h undernitrogen and was concentrated under vacuum to give methyl2-(3-(imino(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)methyl)thioureido)nicotinate (0.8 g, crude).

Methyl-2-((3-(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinate

To a mixture of methyl2-(3-(imino(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)methyl)thioureido)nicotinate(0.8 g, crude) in EtOH (15 mL) was added a solution of iodine (9.20 mg,0.036 mmol) in EtOH (5 mL) and hydrogen peroxide (410.97 mg, 3.62 mmol,30% purity) at 0° C. The mixture was stirred at 25° C. for 2 h. Themixture was quenched by addition of saturated sodium sulfite aqueous (50mL) at 0° C. The mixture was concentrated under vacuum and the aqueousphase was extracted with DCM. The combined organic phases were washedwith brine, dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum to give methyl2-((3-(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinate(1 g, crude).

2-((3-(5-Isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinicAcid

To a mixture of methyl2-((3-(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinate(1 g, crude) in MeOH (30 mL) was added a solution of lithium hydrate(955.00 mg, 22.76 mmol) in H₂O (10 mL). The mixture was stirred at 25°C. for 20 h. and was concentrated to remove the EtOH. The resultingmixture was adjusted to pH of 4 with 6N HCl. The suspension was filteredand the filter cake was collected and dried under vacuum to give2-((3-(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinicacid (0.9 g, crude).

2-((3-(5-Isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylnicotinamide

To a mixture of2-((3-(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinicacid (0.9 g, crude) and dimethylamine hydrochloride (517.58 mg, 6.35mmol) in DMF (20 mL) were added DIPEA (1.37 g, 10.58 mmol, 1.84 mL) andHATU (965.36 mg, 2.54 mmol) at 0° C. The mixture was stirred at 25° C.for 19 h. The mixture was diluted with EtOAc. The organic phase waswashed with brine, dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The products was isolated and purified bystandard methods to give2-((3-(5-isopropoxy-4-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylnicotinamide(95.25 mg, 0.202 mmol, 9.55% yield). LCMS (ESI) m/z 453.3[M+1]⁺.

Example 39:N-(5-(Difluoromethyl)-2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide

Tert-Butyl (2-aminopyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl methyl(2-nitropyridin-3-yl)carbamate (41.5 g,163.87 mmol) in MeOH (600 mL) were added palladium hydroxide/carbon (2g, 20% purity) and Pd/C (2 g, 10% purity) under nitrogen. The mixturewas stirred at 20° C. for 16 h under hydrogen (15 psi). The mixture wasfiltered and the filtrate was concentrated under vacuum to givetert-butyl (2-aminopyridin-3-yl)(methyl)carbamate (32 g, 143.32 mmol,87.46% yield).

Tert-Butyl (2-amino-5-bromopyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl (2-aminopyridin-3-yl)(methyl)carbamate (12 g,53.75 mmol) in THE (120 mL) was added NBS (10.04 g, 56.43 mmol) inportions at 0° C., the mixture was stirred at 20° C. for 1 h. Themixture was concentrated under vacuum to give a residue. The residue waspurified by silica gel column chromatography to give tert-butyl(2-amino-5-bromopyridin-3-yl)(methyl)carbamate (12.8 g, 40.24 mmol,74.88% yield, 95% purity).

Tert-Butyl (2-amino-5-formylpyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-amino-5-bromopyridin-3-yl)(methyl)carbamate (10.5 g, 34.75 mmol) inTHE (100 mL) was added n-BuLi (2.5 M, 50.04 mL) at −70° C. undernitrogen. The mixture was stirred at −70° C. for 0.5 h. Then DMF (7.62g, 104.25 mmol) was added at −70° C. The mixture was stirred at −70° C.for 1 h. The mixture was poured into saturated NH₄Cl and the aqueousphase was extracted with EtOAc. The combined organic phases were washedwith brine, dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by flash silica gelchromatography to give tert-butyl(2-amino-5-formylpyridin-3-yl)(methyl)carbamate (4.7 g, 18.70 mmol,53.83% yield).

Tert-Butyl (2-amino-5-(difluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-amino-5-formylpyridin-3-yl)(methyl)carbamate (4.2 g, 16.71 mmol) inDCM (120 mL) was added diethylaminosulphur trifluoride (5.39 g, 33.43mmol) at 0° C. The mixture was stirred at 10° C. for 2 h. The reactionwas quenched carefully with saturated sodium bicarbonate at 0° C. Theorganic phase was separated and the aqueous phase was extracted withDCM. The combined organic phases were dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby silica gel chromatography to give a solid. The solid was trituratedwith EtOAc. The filter cake was discarded and the filtrate wasconcentrated under vacuum to give crude product. The crude product waspurified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*50 mm*10μm; mobile phase: [H₂O (0.225% FA)-ACN]; B %: 15%-40%, 19 min) followedby lyophilization to give tert-butyl(2-amino-5-(difluoromethyl)pyridin-3-yl)(methyl)carbamate (0.8 g, 2.93mmol, 17.53% yield).

tert-Butyl-(5-(difluoromethyl)-2-isothiocyanatopyridin-3-yl)(methyl)carbamate

To a mixture of thiophosgene (673.20 mg, 5.85 mmol) in DCM (10 mL) wasadded a solution of tert-butyl(2-amino-5-formylpyridin-3-yl)(methyl)carbamate (0.8 g, 2.93 mmol) inDCM (10 mL). The mixture was stirred at 0° C. for 2 h. The mixture wasquenched with H₂O and saturated sodium bicarbonate. The organic phasewas separated and aqueous phase was extracted with DCM and the combinedorganic phases were concentrated in vacuum. The residue was purified bysilica gel chromatography to give tert-butyl(5-(difluoromethyl)-2-isothiocyanatopyridin-3-yl)(methyl)carbamate (0.75g, 2.38 mmol, 81.25% yield).

tert-Butyl-(5-(difluoromethyl)-2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(5-(difluoromethyl)-2-isothiocyanatopyridin-3-yl)(methyl)carbamate (0.35g, 1.11 mmol, 1 eq) and 5-isopropoxypicolinimidamide (198.92 mg, 1.11mmol) in DCM (10 mL) and acetone (10 mL) was added TEA (561.56 mg, 5.55mmol). The mixture was stirred at 30° C. for 16 h under nitrogen and wasconcentrated under vacuum to givetert-butyl-(5-(difluoromethyl)-2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.55 g, crude).

tert-Butyl-(5-(difluoromethyl)-2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(5-(difluoromethyl)-2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.55 g, crude) in EtOH (10 mL) were added iodine (56.45 mg, 0.222 mmol)and hydrogen peroxide (252.19 mg, 2.22 mmol, 30% purity) at 0° C. Themixture was stirred at 15° C. for 1 h. The mixture was quenched withsaturated sodium sulfite (20 mL) at 0° C. and was concentrated to removethe organic solvent. The aqueous phase was diluted with H₂O andextracted with EtOAc. The combined organic phases were dried withanhydrous sodium sulfate, filtered and concentrated. The residue waspurified by silica gel chromatography to give tert-butyl(5-(difluoromethyl)-2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate(0.47 g, 0.954 mmol, 85.80% yield).

5-(Difluoromethyl)-N²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyridine-2,3-diaminehydrochloride

To a mixture of tert-butyl(5-(difluoromethyl)-2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate(0.47 g, 0.954 mmol) in EtOAc (5 mL) was added hydrochloride/EtOAc (4 M,5 mL) at 0° C. The mixture was stirred at 15° C. for 3 h. The mixturewas concentrated under vacuum to give5-(difluoromethyl)-N²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyridine-2,3-diaminehydrochloride (0.4 g, crude).

N-(5-(Difluoromethyl)-2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide

To a mixture of5-(difluoromethyl)-N²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyridine-2,3-diaminehydrochloride (0.4 g, crude) in ACN (15 mL) were added TEA (471.87 mg,4.66 mmol) and Ac₂O (123.78 mg, 1.21 mmol). The mixture was stirred at30° C. for 5 h. The mixture was stirred at 30° C. for 16 h and wasconcentrated under vacuum. The product was isolated and purified bystandard methods to giveN-(5-(difluoromethyl)-2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide(219.91 mg, 0.506 mmol, 54.22% yield). LCMS (ESI): m/z 435.1 [M+1]⁺.

Example 40:2-((3-(4-(Difluoromethyl)-5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylnicotinamide

2-Bromo-5-fluoroisonicotinaldehyde

To a mixture of 2-bromo-5-fluoropyridine (23 g, 130.69 mmol) in THE (200mL) was added lithium diisopropylamide (2 M, 85 mL) at −65° C. slowly,the resulting mixture was stirred at −65° C. for 2 h. Then DMF (19.00 g,259.94 mmol, 20 mL) in THE (30 mL) was added to the mixture at −65° C.slowly and stirred at −65° C. for 1 h. The reaction mixture was pouredinto cold H₂O and saturated sodium bicarbonate aqueous. The aqueousphase was extracted with EtOAc and the combined organic phases werewashed with brine, dried with anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography to give 2-bromo-5-fluoroisonicotinaldehyde (10 g, 49.02mmol, 37.51% yield) and 2-bromo-5-fluoroisonicotinaldehyde (8 g, crude).

2-Bromo-4-(difluoromethyl)-5-fluoropyridine

To a mixture of 2-bromo-5-fluoroisonicotinaldehyde (8 g, crude) in DCM(150 mL) was added N-ethyl-N-(trifluoro-sulfanyl)ethanamine (11.38 g,70.59 mmol, 9.33 mL) dropwise at −20° C. slowly, then the mixture waswarmed to 25° C. and stirred for 3 h. The mixture was poured intosaturated sodium bicarbonate aqueous and stirred for 5 min. The aqueousphase was extracted with DCM. The combined organic phases were washedwith brine, dried with anhydrous sodium sulfate, filtered andconcentrated in vacuum. The residue was purified by silica gelchromatography to give 2-bromo-4-(difluoromethyl)-5-fluoropyridine (5.4g, 23.89 mmol, 60.93% yield).

4-(Difluoromethyl)-5-fluoropicolinonitrile

To a mixture of 2-bromo-4-(difluoromethyl)-5-fluoropyridine (5.4 g,23.89 mmol), zinc cyanide (5.61 g, 47.79 mmol) and zinc (312.49 mg, 4.78mmol) in DMF (50 mL) was added tetrakis (triphenylphosphine) palladium(2.76 g, 2.39 mmol) under nitrogen, then the mixture was stirred at 120°C. for 6 h. The mixture was filtered with a pad of celite and thefiltrate was poured into EtOAc and brine. The aqueous phase wasextracted with EtOAc. The combined organic phases were washed withbrine, dried with anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by silica gel chromatography togive 4-(difluoromethyl)-5-fluoropicolinonitrile (3 g, 17.43 mmol, 72.95%yield).

4-(Difluoromethyl)-5-isopropoxypicolinonitrile

To a mixture of propan-2-ol (1.05 g, 17.43 mmol) in DMF (30 mL) wasadded NaH (1.39 g, 34.86 mmol, 60% purity) at 0° C., then the mixturewas stirred at 25° C. for 0.5 h. Then4-(difluoromethyl)-5-fluoropicolinonitrile (3 g, 17.43 mmol) was addedin portions at 0° C., the resulting mixture was stirred at 25° C. for 2h. The mixture was poured into saturated NH₄Cl aqueous (200 mL). Theaqueous phase was extracted with EtOAc. The combined organic phases werewashed with brine, dried with anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by silica gelchromatography to give 4-(difluoromethyl)-5-isopropoxypicolinonitrile(1.7 g, 8.01 mmol, 45.96% yield).

4-(Difluoromethyl)-5-isopropoxypicolinimidamide

To a mixture of 4-(difluoromethyl)-5-isopropoxypicolinonitrile (1.7 g,8.01 mmol) in MeOH (10 mL) was added a solution of sodium (55.25 mg,2.40 mmol) in MeOH (3 mL) and stirred until solid sodium disappeared.The resulting mixture was stirred at 25° C. for 3 h.

To the mixture was added NH₄Cl (557.11 mg, 10.41 mmol), then heated to70° C. and stirred for 2 h. The hot mixture was filtered and thefiltrate was concentrated under vacuum. The crude product was trituratedwith MTBE (30 mL) and stirred for 0.5 h. The suspension was filtered andthe filtered cake was freed by Amberlyst A 26 in H₂O (20 ml) and ACN (20mL) until pH was greater than 12. Then the mixture was filtered with apad of celite. The filtrate was concentrated to remove ACN and dried bylyophilization to give 4-(difluoromethyl)-5-isopropoxypicolinimidamide(1.8 g, 7.85 mmol, 98.02% yield).

2-Amino-N,N-dimethylnicotinamide

To a mixture of 2-aminonicotinic acid (5 g, 36.20 mmol), HATU (18.5 g,48.65 mmol) and DIPEA (22.26 g, 172.23 mmol, 30 mL) in DMF (50 mL) wasadded dimethylamine (8.5 g, 104.24 mmol, 9.55 mL, HCl) at 0° C., themixture was stirred at 25° C. for 3 h. The mixture was stirred at 25° C.for 13 h and was concentrated to give a residue. The residue waspurified by silica gel column chromatography to give2-amino-N,N-dimethylnicotinamide (3 g, 18.16 mmol, 50.17% yield).

2-Isothiocyanato-N,N-dimethylnicotinamide

To a mixture of thiophosgene (4.18 g, 36.32 mmol, 2.78 mL) in DCM (20mL) was added a solution of 2-amino-N,N-dimethylnicotinamide (3 g, 18.16mmol) in DCM (30 mL) at 0° C., the mixture was stirred at 0° C. undernitrogen for 2 h. The mixture was poured into saturated sodiumbicarbonate, the aqueous phase was extracted with DCM, the combinedorganic phases were concentrated under vacuum to give a mixture. Themixture was purified by silica gel column chromatography to give2-isothiocyanato-N,N-dimethylnicotinamide (3 g, 14.48 mmol, 79.71%yield).

2-(3-((4-(Difluoromethyl)-5-isopropoxypyridin-2-yl)(imino)methyl)thioureido)-2-isothiocyanato-N,N-dimethylnicotinamide-N,N-dimethylnicotinamide

To a mixture of 4-(difluoromethyl)-5-isopropoxypicolinimidamide (0.5 g,2.18 mmol) and 2-isothiocyanato-N,N-dimethylnicotinamide (452.07 mg,2.18 mmol) in DCM (10 mL) and acetone (10 mL) was added TEA (1.10 g,10.91 mmol, 1.52 mL), then the mixture was stirred at 25° C. for 16 hand was concentrated under vacuum to give2-(3-((4-(difluoromethyl)-5-isopropoxypyridin-2-yl)(imino)methyl)thioureido)-N,N-dimethylnicotinamide (1 g, crude).

2-((3-(4-(Difluoromethyl)-5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-amino)-N,N-dimethylnicotinamide

To a mixture of2-(3-((4-(difluoromethyl)-5-isopropoxypyridin-2-yl)(imino)methyl)thioureido)-N,N-dimethylnicotinamide(1 g, crude) in EtOH (10 mL) was added hydrogen peroxide (519.53 mg,4.58 mmol, 30% purity) and a solution of iodine (116.30 mg, 458.21 μmol)in EtOH (3 mL), then the mixture was stirred at 25° C. for 2 h. Themixture was quenched by addition of saturated sodium sulfite aqueous at0° C., then concentrated under vacuum. The aqueous phase was extractedwith DCM. The combined organic phases were washed with brine, dried withanhydrous sodium sulfate, filtered and concentrated under vacuum. Theproduct was isolated and purified by standard methods to give2-((3-(4-(difluoromethyl)-5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylnicotinamide(342.28 mg, 0.788 mmol, 34.39% yield). LCMS (ESI): m/z 435.3 [M+1]⁺.

Example41:5-Isopropoxy-N,N-dimethyl-2-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)isonicotinamide

2-Bromo-5-isopropoxy-N,N-dimethylisonicotinamide

To a mixture of 2-bromo-5-isopropoxyisonicotinic acid (2 g, 7.69 mmol)and oxalyl chloride (2.17 g, 17.14 mmol, 1.50 mL) in DCM (30 mL) wasadded DMF (9.50 mg, 0.129 mmol, 0.01 mL) at 25° C. The mixture wasstirred at 25° C. for 1 h and was concentrated under vacuum to give aresidue. To a mixture of the residue in DCM (30 mL) was added TEA (2.33g, 23.07 mmol, 3.21 mL) and dimethylamine hydrochloride (0.8 g, 9.81mmol, 0.898 mL) at 0° C., the mixture was stirred at 25° C. for 1 h andwas concentrated under vacuum to give a residue. The residue waspurified by silica gel column chromatography to give2-bromo-5-isopropoxy-N,N-dimethylisonicotinamide (2.1 g, crude).

2-Cyano-5-isopropoxy-N,N-dimethylisonicotinamide

To a mixture of 2-bromo-5-isopropoxy-N,N-dimethylisonicotinamide (2 g,crude), zinc cyanide (1.64 g, 13.93 mmol) and zinc (90.00 mg, 1.38 mmol)in DMF (30 mL) was added tetrakis(triphenylphosphine)palladium (1.61 g,1.39 mmol), the mixture was stirred at 120° C. for 14 h under nitrogen.The mixture was filtered through a pad of celite and the filtrate waspoured into H₂O. The mixture was extracted with EtOAc. The combinedorganic phases were washed with brine, and concentrated under vacuum togive a residue. The residue was purified by prep-HPLC (column:Phenomenex Synergi Max-RP 250*50 mm*10 μm; mobile phase: [H₂O (0.225%FA)-ACN]; B %: 25ACN %-55ACN %, 28 min, 60% min) and followed bylyophilization to give 2-cyano-5-isopropoxy-N,N-dimethylisonicotinamide(0.8 g, 3.43 mmol, 49.24% yield).

2-Carbamimidoyl-5-isopropoxy-N,N-dimethylisonicotinamide

A mixture of sodium (47 mg, 2.04 mmol) in MeOH (10 mL) was stirred at25° C. for 10 min. To the mixture was added2-cyano-5-isopropoxy-N,N-dimethylisonicotinamide (0.8 g, 3.43 mmol) at25° C., the mixture was stirred at 40° C. for 4 h. Then to the mixturewas added NH₄Cl (0.29 g, 5.42 mmol), the mixture was stirred at 70° C.for 1.5 h and was concentrated under vacuum to give a residue. Theresidue was triturated with MTBE (20 mL), the precipitate was collectedby filtration and dried under high vacuum to give2-carbamimidoyl-5-isopropoxy-N,N-dimethylisonicotinamide hydrochloride(0.98 g, 3.42 mmol, 99.65% yield).

5-Isopropoxy-N,N-dimethyl-2-(N-((3-methylpyridin-2-yl)carbamothioyl)carbamimidoyl)isonicotinamide

To a mixture of 2-carbamimidoyl-5-isopropoxy-N,N-dimethylisonicotinamide(0.3 g, 1.05 mmol) and 2-isothiocyanato-3-methylpyridine (0.19 g, 1.14mmol) in acetone (30 mL) and DCM (30 mL) was added TEA (1.06 g, 10.46mmol, 1.46 mL). The mixture was stirred at 25° C. for 3 h. To themixture was added 2-isothiocyanato-3-methylpyridine (0.08 g, 0.53 mmol)and TEA (1.06 g, 10.46 mmol, 1.46 mL). Then the mixture was stirred at25° C. for 12 h. The mixture was then stirred at 40° C. for 6 h andconcentrated under vacuum to give a crude product. The crude product wasused directly in the next step.5-isopropoxy-N,N-dimethyl-2-(N-((3-methyl-pyridin-2-yl)carbamothioyl)carbamimidoyl)isonicotinamide(0.7 g, crude).

5-Isopropoxy-N,N-dimethyl-2-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)isonicotinamide

To a mixture of5-isopropoxy-N,N-dimethyl-2-(N-((3-methyl-pyridin-2-yl)carb-amothioyl)carbamimidoyl)isonicotinamide(0.7 g, 1.75 mmol) in EtOH (40 mL) was added iodine (88.00 mg, 346.72μmol) and hydrogen peroxide (413.00 mg, 3.64 mmol, 0.35 mL, 30% purity)at 0° C. The mixture was stirred at 25° C. for 40 min. The mixture wasquenched with saturate sodium sulfite and concentrated under vacuum togive an aqueous phase. The aqueous phase was extracted with DCM. Thecombined organic phases were concentrated under vacuum to give aresidue. The product was isolated and purified by standard methods togive5-isopropoxy-N,N-dimethyl-2-(5-((3-methylpyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)isonicotinamide(134.84 mg, 335.68 μmol, 19.21% yield, 99.2% purity). LCMS (ESI): m/z427.3 [M+1]+.

Example42:1-(4-(6-((3-(5-Cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazin-1-yl)-3,3,3-trifluoropropan-1-oneand1-(4-(6-((3-(5-Cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazin-1-yl)ethanone)

Tert-Butyl 4-(6-nitropyridin-3-yl)piperazine-1-carboxylate

To a mixture of 5-chloro-2-nitropyridine (12.7 g, 80.10 mmol) andtert-butyl piperazine-1-carboxylate (14.92 g, 80.10 mmol) in DMSO (120mL) was added cesium fluoride (14.60 g, 96.13 mmol). The reactionmixture was stirred at 80° C. for 16 h. The reaction mixture was dilutedwith H₂O and extracted with EtOAc. The combined organic layers werewashed with brine, dried over sodium sulfate, filtered and concentratedunder reduced pressure to give a residue. The residue was trituratedwith petroleum ether and EtOAc and filtered to afford a solid. The solidwas purified by column chromatography to give tert-butyl4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (10.2 g, 24.15 mmol,30.15% yield).

Tert-Butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate

Two batches: To a mixture of tert-butyl4-(6-nitropyridin-3-yl)piperazine-1-carboxylate (5 g, 11.84 mmol) inMeOH (200 mL) was added Pd/C (1 g, 10% purity). The mixture was degassedunder vacuum and purged with hydrogen several times. The mixture wasstirred under hydrogen (15 Psi) at 25° C. for 0.5 h. The reactionmixture was filtered and the filter was concentrated under reducedpressure to give a residue. The residue was purified by columnchromatography to give tert-butyl4-(5-aminopyridin-2-yl)piperazine-1-carboxylate (1.5 g, 5.28 mmol,22.31% yield, 98% purity) as solid and tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (5.8 g, 20.42 mmol,86.25% yield) was obtained.

Tert-Butyl 4-(6-isothiocyanatopyridin-3-yl)piperazine-1-carboxylate

To a mixture of di(imidazol-1-yl)methanethione (2.45 g, 13.73 mmol) inDMF (15 mL) was added a solution of tert-butyl4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (3 g, 10.56 mmol) in DMF(15 mL). The mixture was stirred at 25° C. for 0.5 h. The crude producttert-butyl 4-(6-isothiocyanatopyridin-3-yl)piperazine-1-carboxylate(3.38 g, crude) in DMF (30 mL) as a solution was used in the next step.

tert-Butyl-4-(6-(3-((5-cyclopropoxypyridin-2-yl)(imino)methyl)thioureido)pyridin-3-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-(6-isothiocyanatopyridin-3-yl)piperazine-1-carboxylate (3.35 g) in DMF(30 mL) were added diisopropylethylamine (4.05 g, 31.32 mmol) and5-(cyclopropoxy)pyridine-2-carboxamidine (1.85 g, 10.44 mmol). Themixture was stirred at 25° C. for 1 h. The reaction mixture was pouredinto H₂O and diluted with EtOAc. The mixture was extracted with EtOAcand the combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to give tert-butyl4-(6-(3-((5-cyclopropoxypyridin-2-yl)(imino)methyl)thioureido)pyridin-3-yl)piperazine-1-carboxylate(5.2 g, crude).

tert-Butyl-4-(6-((3-(5-cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate

To a mixture of tert-butyl4-(6-(3-((5-cyclopropoxypyridin-2-yl)(imino)methyl)thioureido)pyridin-3-yl)piperazine-1-carboxylate(5.2 g) in EtOH (70 mL) was added a solution of iodine (530 mg, 2.09mmol) in EtOH (10 mL) and hydrogen peroxide (2.37 g, 20.91 mmol, 2.01mL, 30% purity) under nitrogen. The mixture was stirred at 25° C. for 2h. The mixture was cooled and poured into saturated sodium sulphite (100ml). The mixture was triturated with H₂O, filtered and the filter cakedissolved in MeOH and DCM and was concentrated under vacuum. The residuewas triturated with ACN (50 mL) and filtered to give tert-butyl4-(6-((3-(5-cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate(3.8 g, crude).

3-(5-Cyclopropoxypyridin-2-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of tert-butyl4-(6-((3-(5-cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (1 g) in DCM (5 mL) wasadded hydrochloride/dioxane (4 M, 20 mL). The mixture was stirred at 25°C. for 1 h and concentrated to give3-(5-cyclopropoxypyridin-2-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(1 g, crude, HCl). 500 mg of3-(5-cyclopropoxypyridin-2-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)-1,2,4-thiadiazol-5-amineas the free amine was recovered in next acid amine coupling.

1-(4-(6-((3-(5-Cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazin-1-yl)-3,3,3-trifluoropropan-1-oneand1-(4-(6-((3-(5-cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazin-1-yl)ethanone

To a mixture of3-(5-cyclopropoxypyridin-2-yl)-N-(5-(piperazin-1-yl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(500 mg, 1.26 mmol), 3,3,3-trifluoropropanoic acid (243 mg, 1.90 mmol)and DIPEA (490 mg, 3.79 mmol) in DMF (50 mL) was added HATU (721 mg,1.90 mmol) at 0° C. The mixture was stirred at 45° C. for 16 h. Themixture was filtered and the filtrate concentrated to give a residue.The products were isolated and purified by standard methods to give1-(4-(6-((3-(5-cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazin-1-yl)-3,3,3-trifluoropropan-1-one(157.96 mg, 0.308 mmol, 24.34% yield); LCMS (ESI) m/z 506.1 [M+1]⁺ and1-(4-(6-((3-(5-cyclopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)piperazin-1-yl)ethanone(32.64 mg, 0.0724 mmol, 5.72% yield, 97% purity); LCMS (ESI) m/z 438.1[M+1]⁺.

Example 43:1-(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)pyrrolidin-2-one

1-(2-Nitropyridin-3-yl)pyrrolidin-2-one

A mixture of palladium acetate (1 g, 4.45 mmol) and(5-diphenylphosphanyl-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphane(2.61 g, 4.51 mmol) in toluene (130 mL) was stirred at 15° C. for 15 minunder nitrogen. To the mixture were added 3-bromo-2-nitropyridine (4.5g, 22.17 mmol), pyrrolidin-2-one (2.25 g, 26.44 mmol, 2.03 mL), copperiodide (846.00 mg, 4.44 mmol) and cesium carbonate (10.80 g, 33.15mmol), and the mixture was stirred at 75° C. for 4 h under nitrogen. Thereaction mixture was cooled to room temperature. The reaction mixturewas filtered and the filtrate was concentrated to give a residue. Theresidue was purified by silica gel column chromatography to give1-(2-nitropyridin-3-yl)pyrrolidin-2-one (4.5 g, crude).

1-(2-Aminopyridin-3-yl)pyrrolidin-2-one

To a mixture of 1-(2-nitropyridin-3-yl)pyrrolidin-2-one (2.5 g, crude)in trifluoroethanol (50 mL) were added Pd/C (0.5 g, 10% purity) andpalladium hydroxide/carbon (0.5 g, 20% purity) under nitrogen. Thereaction mixture was degassed under vacuum and purged with hydrogen for3 times. The reaction mixture was stirred at 60° C. under hydrogen (15psi) for 3 h. The reaction mixture was filtered and the filtrate wasconcentrated to afford a crude product. The crude product was purifiedby silica gel column chromatography to give1-(2-aminopyridin-3-yl)pyrrolidin-2-one (2.6 g, 10.42 mmol).

1-(2-Isothiocyanatopyridin-3-yl)pyrrolidin-2-one

To a mixture of thiocarbonyl dichloride (1.50 g, 13.05 mmol, 1 mL) inDCM (10 mL) was added a solution of1-(2-amino-3-pyridyl)pyrrolidin-2-one (1.5 g, 6.01 mmol) in DCM (5 mL)dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. To themixture was added saturated sodium bicarbonate aqueous and the mixturewas separated layers. The aqueous phase was extracted with DCM. Thecombined organic phases were concentrated under vacuum to give aresidue. The residue was purified by silica gel column chromatography togive 1-(2-isothiocyanatopyridin-3-yl)pyrrolidin-2-one (1.2 g, 5.47 mmol,91.06% yield).

5-Isopropoxy-N-((3-(2-oxopyrrolidin-1-yl)pyridin-2-yl)carbamothioyl)picolinimidamide

To a mixture of 1-(2-isothiocyanatopyridin-3-yl)pyrrolidin-2-one (0.35g, 1.60 mmol) and 5-isopropoxypicolinimidamide (0.29 g, 1.62 mmol) inDCM (7 mL) and acetone (7 mL) was added TEA (1.11 mL, 7.96 mmol). Themixture was stirred at 25° C. for 3 h. To the mixture was addedsaturated sodium hydrogen bicarbonate, the mixture was was extractedwith DCM. The combined organic phases were concentrated to give5-isopropoxy-N-((3-(2-oxopyrrolidin-1-yl)pyridin-2-yl)carbamothioyl)picolinimidamide(0.63 g, crude).

1-(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)pyrrolidin-2-one

To a mixture of 5-isopropoxy-N-((3-(2-oxopyrrolidin-1-yl)pyridin-2-yl)carbamothioyl)picolinimidamide (0.63 g, crude) in EtOH (10 mL) was addeda solution of iodine (0.05 g, 0.197 mmol) in EtOH (5 mL) and hydrogenperoxide (0.34 mL, 54 mmol, 30% purity) at 0° C. Then the mixture wasstirred at 25° C. for 1 h. To the mixture was added saturated sodiumsulfite, the mixture was extracted with DCM, then the combined organicphases were concentrated to give a crude product. The product wasisolated and purified by standard methods to give1-(2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)pyrrolidin-2-one (284.3 mg, 0.716 mmol, 99.9% purity). LCMS(ESI): m/z 397.2 [M+1]+.

Example 44:N³,N³-Dimethyl-N²-(3-(2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine

tert-Butyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a mixture of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine hydrochloride (4g, 25.54 mmol) and TEA (7.75 g, 76.62 mmol) in DCM (120 mL) was addedBoc-anhydride (6.69 g, 30.65 mmol) at 0° C. The mixture was stirred at10° C. for 3 h and concentrated under vacuum. The residue was purifiedby silica gel chromatography to give tert-butyl1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (3.4 g, 15.44 mmol, 60.44%yield).

2-(tert-Butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine 5-oxide

To a mixture of tert-butyl 1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(3.40 g, 15.44 mmol) in DCM (100 mL) was added m-CPBA (4.00 g, 18.52mmol, 80% purity) at 0° C. The mixture was stirred at 15° C. for 2 h andconcentrated under vacuum. The residue was purified by silica gelchromatography to give2-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine 5-oxide(3.5 g, 12.44 mmol, 80.62% yield, 84% purity).

Tert-Butyl 4-cyano-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a mixture of2-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine 5-oxide(3.5 g, 12.44 mmol) and trimethylsilyl cyanide (6.17 g, 62.20 mmol) inDCM (100 mL) was added dimethylcarbamic chloride (6.69 g, 62.20 mmol,5.72 mL). The mixture was stirred at 10° C. for 16 h. The reactionmixture was poured into 100 mL 10% potassium carbonate H₂O solution. Theaqueous phase was extracted with DCM. The combined organic phases weredried with anhydrous sodium sulfate, filtered and concentrated invacuum. The residue was purified by silica gel chromatography to givetert-butyl 4-cyano-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (2.7 g,11.01 mmol, 88.49% yield).

tert-Butyl-4-carbamimidoyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylatehydrochloride

Sodium (140.60 mg, 6.12 mmol) was added into MeOH (30 mL). To themixture was added tert-butyl4-cyano-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (3 g, 12.23 mmol).The mixture was stirred at 15° C. for 3 h. Ammonia chloride (981.36 mg,18.35 mmol) was added. The mixture was stirred at 70° C. for 2 h and wasconcentrated under vacuum. The residue was diluted with EtOH and themixture was stirred at 70° C. for 10 min. The mixture was filtered andthe filtrate was concentrated to give a solid. The solid was trituratedwith DCM (30 mL) and the filtrate was concentrated to give tert-butyl4-carbamimidoyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylatehydrochloride (3 g, crude).

tert-Butyl-4-(N-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)carbamimidoyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a mixture of 2-isothiocyanato-N,N-dimethylpyridin-3-amine (1.2 g,6.69 mmol) and tert-butyl4-carbamimidoyl-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylatehydrochloride (2.00 g, 6.69 mmol) in DCM (30 mL) and acetone (30 mL) wasadded TEA (6.77 g, 66.95 mmol). The mixture was stirred at 15° C. for 3h under nitrogen and concentrated under vacuum. The residue was pouredinto H₂O. The aqueous phase was extracted with EtOAc and the combinedorganic phases were dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum to give tert-butyl4-(N-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)carbamimidoyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(4 g, 5.98 mmol, 89.31% yield, 66% purity).

tert-Butyl-4-(5-((3-(dimethylamino)pyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate

To a mixture oftert-butyl-4-(N-((3-(dimethylamino)pyridin-2-yl)carbamothioyl)carbamimidoyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(4 g, 5.98 mmol, 66% purity) in EtOH (60 mL) were added iodine (303.50mg, 1.20 mmol) and hydrogen peroxide (2.03 g, 17.94 mmol, 1.72 mL, 30%purity) at 0° C. The mixture was stirred at 15° C. for 0.5 h. Themixture was quenched with saturated sodium sulfite at 0° C. The mixturewas concentrated to remove the organic solvent. The aqueous phase wasdiluted with H₂O and extracted with EtOAc. The combined organic phaseswere dried with anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by silica gel chromatography to give tert-butyl4-(5-((3-(dimethylamino)pyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(2.6 g, 4.91 mmol, 82.12% yield, 83% purity).

N²-(3-(2,3-Dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diaminetrifluoroacetic Acid

To a mixture of tert-butyl4-(5-((3-(dimethylamino)pyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate(1 g, 1.89 mmol) in DCM (10 mL) was added trifluoroacetic acid (3.23 g,28.33 mmol, 2.10 mL) at 0° C. The mixture was stirred at 20° C. for 2hand was concentrated under vacuum to giveN²-(3-(2,3-Dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diaminetrifluoroacetic acid (1.1 g, crude).

N³,N³-Dimethyl-N²-(3-(2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine

To a mixture ofN²-(3-(2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,2,4-thiadiazol-5-yl)-N³,N³-dimethylpyridine-2,3-diaminetrifluoroacetic acid (1.1 g, 2.43 mmol) in MeOH (20 mL) was added TEA(490.95 mg, 4.85 mmol) at 0° C. The mixture was stirred at 0° C. for 0.1h. Then formaldehyde (984.32 mg, 12.13 mmol), acetic acid (437.04 mg,7.28 mmol) and sodium cyanoborohydride (457.34 mg, 7.28 mmol) were addedat 0° C. The mixture was stirred at 20° C. for 1 h and was concentratedin reduced pressure. The residue was poured into H₂O and saturatedsodium bicarbonate. The aqueous phase was extracted with EtOAc. Thecombined organic phases were dried with anhydrous sodium sulfate,filtered and concentrated in vacuum. The product was isolated andpurified by standard methods to giveN³,N³-dimethyl-N²-(3-(2-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-4-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamineformic acid (394.61 mg, 0.959 mmol, 39.54% yield). LCMS (ESI) m/z 354.3[M+1]⁺.

Example 45:N-Methyl-N-(2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamide

Tert-Butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a mixture of 1H-pyrrolo[2,3-c]pyridine (50 g, 423.24 mmol), DMAP(2.59 g, 21.16 mmol) and TEA (85.66 g, 746.48 mmol) in DCM (500 mL) wasadded Boc-anhydride (96.99 g, 444.4 mmol) was added dropwise at 0° C.The mixture was stirred at 25° C. for 3 h and was concentrated undervacuum. The residue was purified by silica gel chromatography to givetert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (90 g, 412.37 mmol,97.43% yield).

Tert-Butyl 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a mixture of tert-butyl 1H-pyrrolo[2,3-c]pyridine-1-carboxylate (90g, 412.37 mmol) in MeOH (1000 mL) were added Pd/C (5 g, 10% purity) andpalladium hydroxide/carbon (5 g, 20% purity) under nitrogen. The mixturewas stirred at 25° C. for 6 h under hydrogen (50 psi). The mixture wasfiltered and the filtrate was concentrated under vacuum. The residue waspurified by silica gel chromatography to give tert-butyl2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (86 g, 390.44 mmol,94.68% yield).

1-(tert-Butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine 6-oxide

Two batches: To a mixture of tert-butyl2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (43 g, 195.2 mmol)in DCM (400 mL) was added m-CPBA (46.32 g, 214.74 mmol, 80% purity) at0° C. The mixture was stirred at 25° C. for 2 h. And was concentratedunder vacuum at 25° C. The mixture was purified by silica gelchromatography to tert-butyl6-oxido-2,3-dihydropyrrolo[2,3-c]pyridin-6-ium-1-carboxylate (42 g,177.77 mmol, 45.53% yield, 100% purity). The crude product was purifiedby silica gel chromatography to give tert-butyl6-oxido-2,3-dihydropyrrolo[2,3-c]pyridin-6-ium-1-carboxylate (43 g,180.18 mmol, 46.15% yield).

tert-Butyl-7-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylateand tert-butyl5-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a mixture of1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine 6-oxide(43 g, 180.18 mmol) in DCM (650 mL) was added N,N-dimethylcarbamoylchloride (58.13 g, 540.53 mmol) dropwise at 0° C. Then trimethylsilylcyanide (53.62 g, 540.53 mmol) was added dropwise at 0° C. The mixturewas stirred at 25° C. for 16 h. The reaction mixture was poured into 400mL of 20% potassium carbonate H₂O solution. The organic phase wasseparated and the aqueous phase was extracted with DCM. The combinedorganic phases were washed with brine, dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The residue was purifiedby silica gel chromatography to give tert-butyl5-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (16 g, 65.2mmol, 18.1% yield) and a mixture of tert-butyl7-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate andtert-butyl 5-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(78 g, crude). The mixture of tert-butyl7-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate andtert-butyl 5-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(78 g, crude) was purified by reverse MPLC (MeCN/H₂O, formic acid). Theeluent was concentrated to remove ACN and the aqueous phase wasextracted with EtOAc. The combined organic phases were dried withanhydrous sodium sulfate, filtered and concentrated in vacuum to givetert-butyl 7-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(42 g, 171.24 mmol) and tert-butyl5-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (11 g, 44.85mmol).

2,3-Dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile

To a mixture of tert-butyl5-cyano-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (10 g, 40.77mmol) in DCM (80 mL) was added trifluoroacetic acid (80 mL) at 0° C. Themixture was stirred at 0° C. for 2 h and was concentrated under vacuumat 25° C. The residue was diluted with DCM and cold saturated sodiumbicarbonate. The organic phase was separated and the aqueous phase wasextracted with DCM. The combined organic phases were dried withanhydrous sodium sulfate, filtered and concentrated in vacuum to give2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile (7 g, crude).

1-Methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile

To a mixture of 2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile (7g, crude), acetic acid (2.90 g, 48.22 mmol) and formaldehyde (19.57 g,241.11 mmol, 17.95 mL, 37%) in MeOH (150 mL) was added sodiumcyanoborohydride (6.06 g, 96.44 mmol) at 0° C. The mixture was stirredat 25° C. for 16 h and was concentrated under vacuum. The residue waspoured into cold saturated sodium bicarbonate and the aqueous phase wasextracted with DCM. The combined organic phases were dried withanhydrous sodium, filtered and concentrated in vacuum. The residue waspurified by silica gel chromatography to give 3.5 g of product and 3 gof crude product. 3 g of crude product was purified by reverse MPLC(1/1000, FA) to give 0.8 of product. Two batches products were combinedto give 1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile(4.3 g, 27.01 mmol, 56.05% yield, 100% purity).

1-Methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamideHydrochloride

To the mixture of1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile (4.3 g,27.01 mmol) in MeOH (60 mL) was added sodium methoxide (729.65 mg, 13.51mmol)(freshly prepared). The mixture was stirred at 30° C. for 16 h.NH₄Cl (2.17 g, 40.52 mmol) was added. The mixture was stirred at 70° C.for 1 h. and was concentrated under vacuum. The residue was diluted with150 mL of EtOH and stirred at 80° C. for 0.5 h. The mixture was filteredand the filtrate was concentrated to give a solid. The solid wastriturated with MTBE (100 mL) and filtered. The filter cake wascollected dried to give1-methyl-2,3-dihydropyrrolo[2,3-c]pyridine-5-carboxamidine hydrochloride(4 g, 18.81 mmol, 69.64% yield). The filtrate was concentrated to give1-methyl-2,3-dihydropyrrolo[2,3-c]pyridine-5-carbonitrile (1 g, crude).

tert-Butyl-(2-(3-(Imino(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate

To a 1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamidehydrochloride (3 g, 14.11 mmol) and tert-butyl(2-isothiocyanatopyridin-3-yl)(methyl)carbamate (3.74 g, 14.11 mmol) inDMF (100 mL) was added triethylamine (7.14 g, 70.53 mmol, 9.82 mL, 5eq). The mixture was stirred at 30° C. for 16 h under nitrogen. Themixture was poured into H₂O and the aqueous phase was extracted withEtOAc. The combined organic phases were washed with brine, dried withanhydrous sodium sulfate, filtered and concentrated in vacuum to givetert-butyl(2-(3-(imino(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(6 g, crude).

Tert-ButylMethyl(2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate

To a mixture of tert-butyl(2-(3-(imino(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(6.5 g, crude) in EtOH (100 mL) were added iodine (747.26 mg, 2.94 mmol)and hydrogen peroxide (3.34 g, 29.44 mmol, 30% purity) at 0° C. Themixture was stirred at 20° C. for 1 h. The mixture was quenched withsaturated sodium sulfite at 0° C. and was concentrated to remove theorganic solvent. The aqueous phase was diluted with H₂O and extractedwith DCM. The combined organic phases were dried with anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel chromatography to give 2.7 g of crude product. The crude product wastriturated with 20 mL of MeOH to give tert-butylmethyl(2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(2.1 g, 4.78 mmol, 32.46% yield).

N³-Methyl-N²-(3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine

To a mixture of tert-butylmethyl(2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(2.10 g, 4.78 mmol) in EtOAc (50 mL) was added hydrochloride/EtOAc (4 M,50 mL) at 0° C. The mixture was stirred at 30° C. for 0.5 h and wasconcentrated under vacuum to giveN³-methyl-N²-(3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diaminehydrochloride (1.8 g, crude).

N-Methyl-N-(2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamide

To a mixture ofN³-methyl-N²-(3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diaminehydrochloride (1.8 g, 4.79 mmol) and Ac₂O (733.32 mg, 7.18 mmol) in ACN(40 mL) was added TEA (2.42 g, 23.94 mmol, 3.33 mL). The mixture wasstirred at 45° C. for 16 h and was concentrated under vacuum. Theproduct was isolated and purified by standard methods to giveN-methyl-N-(2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamideformic acid (808.16 mg, 1.88 mmol, 39.28% yield) andN³-methyl-N²-(3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine(2 g, crude). LCMS (ESI): m/z 382.2 [M+1]⁺.

Example 46:N-(2-((3-(2,2-Dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide

1-(3-Bromopyridin-4-yl)-2-methylpropan-2-ol

In two batches, LDA (2 M, 87.20 mL) was added to a mixture of3-bromo-4-methyl-pyridine (25 g, 145.33 mmol, 16.13 mL) in THE (250 mL)at 0° C., the mixture was stirred at 0° C. for 1 h.

To the mixture was added acetone (16.88 g, 290.66 mmol, 21.37 mL) at 0°C. in one portion, the mixture was stirred at 20° C. for 3 h. The 2batches mixture were combined and quenched with saturated NH₄Cl, theaqueous phase was extracted with EtOAc. The combined organic phases wereconcentrated under vacuum to give a residue. The residue was purified bysilica gel column chromatography to give1-(3-bromopyridin-4-yl)-2-methylpropan-2-ol (39 g, 169.49 mmol, 58.31%yield).

2,2-Dimethyl-2,3-dihydrofuro[2,3-c]pyridine

To a mixture of 1-(3-bromopyridin-4-yl)-2-methylpropan-2-ol (39 g,169.49 mmol), cesium carbonate (110.45 g, 338.98 mmol) in toluene (350mL) was added cuprous iodide (3.23 g, 16.95 mmol) and 8-hydroxyquinoline(3.69 g, 25.42 mmol). The mixture was stirred at 120° C. for 24 h undernitrogen. The mixture was filtered through a pad of celite and silicagel, the filtrate was concentrated under vacuum to give a residue. Theresidue was purified by silica gel column chromatography to give2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine (18 g, 120.65 mmol, 71.19%yield).

2,2-Dimethyl-2,3-dihydrofuro[2,3-c]pyridine 6-oxide

To a mixture of 2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine (18 g,120.65 mmol) in DCM (150 mL) was added m-CPBA (26.23 g, 121.59 mmol, 80%purity) at 0° C., the mixture was stirred at 20° C. for 4 h. The mixturewas purified directly, without work-up. The mixture was purified bysilica gel column chromatography to give2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine 6-oxide (18 g, 108.97 mmol,90.31% yield).

2,2-Dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carbonitrile

To a mixture of 2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine 6-oxide (18g, 108.97 mmol) in DCM (150 mL) were added trimethylsilyl cyanide (32.43g, 326.90 mmol, 40.90 mL) and N,N-dimethylcarbamoyl chloride (35.15 g,326.90 mmol, 30.05 mL), the mixture was warmed to 20° C. under 2 h andstirred at 20° C. for 12 h. The mixture was poured into saturated sodiumbicarbonate, the aqueous phase was extracted with DCM, and the combinedorganic phases were concentrated under vacuum to give a residue. Theresidue was purified by silica gel column chromatography to give2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carbonitrile (1.6 g, 9.18mmol, 8.43% yield) and2,2-dimethyl-3H-furo[2,3-c]pyridine-7-carbonitrile (15 g, 86.11 mmol,79.02% yield).

2,2-Dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboximidamide

To a mixture of2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carbonitrile (1.8 g, 10.33mmol) in MeOH (10 mL) was added sodium methoxide (167.47 mg, 3.10 mmol).The mixture was stirred at 20° C. for 14 h. To the mixture was addedsodium methoxide (111.65 mg, 2.07 mmol). The mixture was stirred at 30°C. for 2 h. To the mixture was added NH₄Cl (829.09 mg, 15.50 mmol). Themixture was stirred at 70° C. for 1 h and was concentrated under vacuumto give a residue. The residue was triturated with MTBE (60 mL), thefilter cake was collected. To a mixture of the filter cake in ACN:H₂O(2:1, 100 mL) was added Amberlyst A-26 (2 g), the mixture was stirred at20° C. for 30 min, the mixture was filtered and the filtrate was driedby lyophilization to give2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboximidamide (1.8 g,7.91 mmol, 76.51% yield).

tert-Butyl(2-(3-((2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)(imino)methyl)thioureido)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-isothiocyanatopyridin-3-yl)(methyl)carbamate (0.5 g, 1.88 mmol) and2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridine-5-carboximidamide (360 mg,1.88 mmol) in acetone (30 mL) and DCM (30 mL) was added TEA (953.43 mg,9.42 mmol, 1.31 mL). The mixture was stirred at 30° C. for 2 h undernitrogen and was concentrated under vacuum to give tert-butyl(2-(3-((2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)(imino)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.86 g, crude).

tert-Butyl-(2-((3-(2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-(3-((2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)(imino)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.86 g, crude) in EtOH (30 mL) were added iodine (95.62 mg, 0.376 mmol)and hydrogen peroxide (427 mg, 3.77 mmol, 30% purity) at 0° C. Themixture was stirred at 20° C. for 1 h. The mixture was quenched withsaturated sodium sulfite at 0° C. and was concentrated. The aqueousphase was diluted with H₂O and extracted with EtOAc. The combinedorganic phases were dried with anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel chromatography togive tert-butyl(2-((3-(2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate (0.55 g, 1.21 mmol, 64.24% yield).

N²-(3-(2,2-Dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyridine-2,3-diaminehydrochloride

To a mixture of tert-butyl(2-((3-(2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate(0.55 g, 1.21 mmol) in EtOAc (5 mL) was added hydrochloride/EtOAc (4 M,10 mL) The mixture was stirred at 20° C. for 1 h and was concentratedunder vacuum to giveN²-(3-(2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyridine-2,3-diaminehydrochloride (0.47 g, crude).

N-(2-((3-(2,2-Dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide

To a mixture ofN²-(3-(2,2-dimethyl-2,3-dihydrofuro[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyridine-2,3-diaminehydrochloride (0.47 g, crude) and TEA (608.35 mg, 6.01 mmol) in ACN (20mL) was added Ac₂O (159.57 mg, 1.56 mmol). The mixture was stirred at30° C. for 16 h and was concentrated under vacuum. The product wasisolated and purified by standard methods to giveN-[2-[[3-(2,2-dimethyl-3H-furo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl]amino]-3-pyridyl]-N-methyl-acetamide(182.76 mg, 0.461 mmol, 38.30% yield). LCMS (ESI): m/z 397.2 [M+1]⁺.

Example 47:3-(5-Isopropoxypyridin-2-yl)-N-isopropyl-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

N-Isopropyl-3-methylpyridin-2-amine

To a mixture of 3-methylpyridin-2-amine (3 g, 27.74 mmol) in THE (60 mL)was added butyl lithium (2.5 M, 13.32 mL) slowly at −70° C. undernitrogen. The mixture was stirred at 0° C. for 30 min. Then2-iodopropane (5.19 g, 30.51 mmol) in THF (5 mL) was added slowly at 0°C. and the mixture was stirred at 25° C. for 16 h. The mixture wasstirred at 65° C. for 16 h. The mixture was quenched with saturatedNH₄Cl at 0° C. and the resulting mixture was extracted with EtOAc. Thecombined organic phases were washed with brine, dried over sodiumsulfate, filtered and concentrated at reduced pressure to give aresidue. The residue was purified by silica gel chromatography to giveN-isopropyl-3-methyl-pyridin-2-amine (1.3 g, 8.65 mmol, 31.20% yield).

O-Phenyl isopropyl(3-methylpyridin-2-yl)carbamothioate

To a mixture of N-isopropyl-3-methyl-pyridin-2-amine (1.20 g, 7.99 mmol)and potassium carbonate (3.31 g, 23.96 mmol) in THE (20 mL) was addedO-phenyl carbonochloridothioate (2.76 g, 15.98 mmol) which was dissolvedwith THE (5 mL) slowly at 0° C. under nitrogen. The mixture was stirredat 25° C. for 16 h and then filtered and the filtrate was concentratedat reduced pressure to give a residue. The residue was purified bysilica gel chromatography to give O-phenylisopropyl(3-methylpyridin-2-yl)carbamothioate (2.2 g, 7.37 mmol, 92.32%yield, 96% purity).

5-Isopropoxy-N-(isopropyl(3-methylpyridin-2-yl)carbamothioyl)picolinimidamide and O-phenylisopropyl(3-methylpyridin-2-yl)carbamothioate

To a mixture of O-phenyl isopropyl(3-methylpyridin-2-yl)carbamothioate(1.54 g, 5.36 mmol) and 5-isopropoxypicolinimidamide (1.15 g, 6.44 mmol)in anhydrous DMSO (15 mL) was added potassium tert-butoxide (1 M, 6.44mL) slowly. The mixture was stirred at 25° C. for 16 h. The mixture waspoured into H₂O and the resulting mixture was extracted with EtOAc. Thecombined organic phases were washed with brine, dried over sodiumsulfate, filtered and concentrated at reduced pressure to give aresidue. The residue was purified by silica gel chromatography to give5-isopropoxy-N-(isopropyl(3-methylpyridin-2-yl)carbamothioyl)picolinimidamide(0.42 g, 1.13 mmol, 21.08% yield) and O-phenylisopropyl(3-methylpyridin-2-yl)carbamothioate (1 g, 3.49 mmol, 65.10%yield).

3-(5-Isopropoxypyridin-2-yl)-N-isopropyl-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a mixture of5-isopropoxy-N-(isopropyl(3-methylpyridin-2-yl)carbamothioyl)picolinimidamide (0.42 g, 1.13 mmol) and hydrogen peroxide (256 mg, 2.26mmol, 30% purity) in EtOH (10 mL) was added iodine (57.39 mg, 0.226mmol). The mixture was stirred at 25° C. for 1 h. The mixture wasquenched with saturated sodium sulfite at 0° C. and the resultingmixture was concentrated at reduced pressure to give a residue. Theresidue was diluted with H₂O and the aqueous phase was extracted withEtOAc, the combined organic phases were washed with brine, dried oversodium sulfate, filtered and concentrated at reduced pressure to give aresidue. The product was isolated and purified by standard methods togive3-(5-isopropoxypyridin-2-yl)-N-isopropyl-N-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-5-amineformic acid (254.92 mg, 0.607 mmol, 53.72% yield). LCMS (ESI): m/z 370.1[M+1]+.

Example 48:5-(5-Isopropoxypyridin-2-yl)-N-(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-amine

5-(Prop-1-en-2-yl)-4-(trifluoromethyl)pyridin-2-amine

To a mixture of 5-bromo-4-(trifluoromethyl)pyridin-2-amine (20 g, 82.98mmol), potassium hydride;trifluoro(isopropenyl)boron (18.42 g, 124.48mmol) and cesium carbonate (54.08 g, 165.97 mmol) in dioxane (500 mL)and H₂O (50 mL) was addedbis(diphenylphosphino)ferrocene]dichloropalladium (3.04 g, 4.15 mmol)under nitrogen. The mixture was then stirred at 80° C. for 5 h. Themixture was filtered and the filtrate was concentrated to give theaqueous phase. The aqueous phase was extracted with EtOAc. The organicphase was washed with brine, dried with anhydrous sodium sulfate,filtered and concentrated in vacuum. The residue was purified by silicagel chromatography to give5-(prop-1-en-2-yl)-4-(trifluoromethyl)pyridin-2-amine (13 g, 51.44 mmol,61.99% yield).

5-Isopropyl-4-(trifluoromethyl)pyridin-2-amine

To a mixture of 5-(prop-1-en-2-yl)-4-(trifluoromethyl)pyridin-2-amine(13 g, 51.44 mmol) in MeOH (180 mL) was added Pd/C (800 mg, 10% purity)and palladium hydroxide (800 mg, 20% purity). The mixture was stirred at25° C. for 16 h under hydrogen (15 psi). The mixture was filtered andthe filtrate was concentrated to give 12 g of crude product as solid. Toa mixture of 12 g of crude product in MeOH (150 mL) was added Pd/C (600mg, 10% purity) and palladium hydroxide (600 mg, 20% purity). Themixture was stirred at 15° C. for 5 h under hydrogen (15 psi) and thenfor an additional 16 h at 15° C. under hydrogen (15 psi). The mixturewas filtered and the filtrate was concentrated to give 12 g of crudeproduct. To a mixture of5-(prop-1-en-2-yl)-4-(trifluoromethyl)pyridin-2-amine (12 g, crude) inMeOH (100 mL) were added palladium hydroxide (0.4 g, 20% purity) andPd/C (0.5 g, 10% purity) under nitrogen. The mixture was stirred at 15°C. for 16 h under hydrogen (15 psi). HNMR of a sample showed 10% ofdouble bond remained. The mixture was stirred at 15° C. for 16 h underhydrogen (15 psi). The mixture was filtered and the filtrate wasconcentrated to give 5-isopropyl-4-(trifluoromethyl)pyridin-2-amine (12g, 58.77 mmol).

5-Isopropyl-2-isothiocyanato-4-(trifluoromethyl)pyridine

To a mixture of thiophosgene (2.25 g, 19.59 mmol) in DCM (50 mL) wasadded a mixture of 5-isopropyl-4-(trifluoromethyl)pyridin-2-amine (2 g,9.79 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at 0° C. for1 h. The saturated sodium bicarbonate was added to the mixture untilpH=8, then resulting mixture was extracted with DCM. The combinedorganic phases were concentrated. The residue was purified by columnchromatography to give5-isopropyl-2-isothiocyanato-4-(trifluoromethyl)pyridine (0.9 g, 3.65mmol, 37.31% yield).

2-(5-Isopropoxypicolinoyl)-N-(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)Hydrazinecarbothioamide

To a mixture of 5-isopropyl-2-isothiocyanato-4-(trifluoromethyl)pyridine(0.5 g, 2.03 mmol) in DCM (20 mL) was added5-isopropoxypicolinohydrazide (455.61 mg, 2.03 mmol). The mixture wasstirred at 15° C. for 16 h and was concentrated to give 0.9 g of crudeproduct. 0.8 g of crude product was purified by silica gelchromatography to give2-(5-isopropoxypicolinoyl)-N-(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)hydrazinecarbothioamide(0.9 g, 1.53 mmol, 75.30% yield, 75% purity).

5-(5-Isopropoxypyridin-2-yl)-N-(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-amine

To a mixture of2-(5-isopropoxypicolinoyl)-N-(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)hydrazinecarbothioamide(0.85 g, 1.44 mmol) in DMSO (20 mL) was added EDCI (553.65 mg, 2.89mmol). The mixture was stirred at 60° C. for 2 h. The mixture was pouredinto 100 mL of H₂O and diluted with 200 mL of EtOAc. The organic phasewas separated and washed with brine, dried with anhydrous sodiumsulfate, filtered and concentrated in vacuum. The product was isolatedand purified by standard methods to give5-(5-isopropoxypyridin-2-yl)-N-(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)-1,3,4-oxadiazol-2-amine(211.6 mg, 0.506 mmol, 35.03% yield). LCMS (ESI) m/z 408.1 [m+1]⁺.

Example 49:N²-(5-(5-Methoxypyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-N³,N³-dimethylpyridine-2,3-diamine

Methyl 5-isopropoxypyrazine-2-carboxylate

To the mixture of methyl 5-chloropyrazine-2-carboxylate (5 g, 28.97mmol) and propan-2-ol (1.92 g, 31.87 mmol, 2.44 mL) in DMF (50 mL) wasadded cesium carbonate (18.88 g, 57.95 mmol). The mixture was stirred at25° C. for 16 h. To the mixture was added cesium carbonate (18.88 g,57.95 mmol) and propan-2-ol (2.61 g, 43.46 mmol, 3.33 mL). The mixturewas stirred at 30° C. for 24 h. To the mixture was added EtOAc (250 mL),the mixture was filtered. The filtrate was washed with brine, dried withanhydrous sodium sulfate, concentrated under reduce pressure to give aresidue. The residue was purified by silica gel chromatography to givemethyl 5-isopropoxypyrazine-2-carboxylate (1.65 g, 7.99 mmol, 27.57%yield, 95% purity) and 2.1 g crude product. Then 2.1 g crude productpurified by silica gel chromatography to give to give methyl5-isopropoxypyrazine-2-carboxylate (0.9 g, 4.59 mmol, 15.83% yield).

5-Methoxypyrazine-2-carbohydrazide

A mixture of methyl 5-isopropoxypyrazine-2-carboxylate (1.65 g, 7.99mmol) and hydrazine hydrate (479.93 mg, 9.59 mmol, 465.95 μL) in MeOH(20 mL) was stirred at 70° C. for 10 h. The reaction mixture wassuspended and the suspension filtered to give5-methoxypyrazine-2-carbohydrazide (0.8 g, 4.76 mmol, 59.55% yield).

N-(3-(Dimethylamino)pyridin-2-yl)-2-(5-methoxypyrazine-2-carbonyl)Hydrazinecarbothioamide

A mixture of 5-methoxypyrazine-2-carbohydrazide (0.8 g, 4.76 mmol) and2-isothiocyanato-N,N-dimethyl-pyridin-3-amine (730.83 mg, 4.08 mmol) inDCM (20 mL) was stirred at 20° C. for 16 h. The mixture was suspendedand concentrated under reduced pressure to give a residue. Then theresidue was triturated with MeOH (20 mL) to give a mixture of5-methoxypyrazine-2-carbohydrazide andN-(3-(dimethylamino)pyridin-2-yl)-2-(5-methoxypyrazine-2-carbonyl)hydrazinecarbothioamide(1.4 g, crude). A mixture of 5-methoxypyrazine-2-carbohydrazide andN-(3-(dimethylamino)pyridin-2-yl)-2-(5-methoxypyrazine-2-carbonyl)hydrazinecarbothioamide(1.4 g, crude) and 2-isothiocyanato-N,N-dimethylpyridin-3-amine (400 mg,2.23 mmol) in DCM (40 mL) was stirred at 20° C. for 16 h. The mixturewas filtered to give filter cake.N-(3-(dimethylamino)pyridin-2-yl)-2-(5-methoxypyrazine-2-carbonyl)hydrazinecarbothioamide(0.8 g, 2.30 mmol, 88.39% yield) and the filtrate was concentrated togive a crude product. The crude product was purified by columnchromatography to giveN-(3-(dimethylamino)pyridin-2-yl)-2-(5-methoxypyrazine-2-carbonyl)hydrazinecarbothioamide(0.6 g, 1.73 mmol, 66.37% yield).

N²-(5-(5-Methoxypyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-N³,N³-dimethylpyridine-2,3-diamine

A mixture ofN-(3-(dimethylamino)pyridin-2-yl)-2-(5-methoxypyrazine-2-carbonyl)hydrazinecarbothioamide(0.7 g, 2.01 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (772.56 mg, 4.03 mmol) in DMSO (20 mL) was stirred at 60°C. for 2 h. The mixture was diluted with H₂O, the resulting mixture wasextracted with EtOAc. The combined organic phases were washed withbrine, dried with anhydrous sodium sulfate, concentrated under reducepressure to give the crude product. The product was isolated andpurified by standard methods to giveN²-(5-(5-methoxypyrazin-2-yl)-1,3,4-oxadiazol-2-yl)-N³,N³-dimethylpyridine-2,3-diamine(179.70 mg, 0.500 mmol, 24.82% yield, formic acid). LCMS (ESI): m/z314.1 [M+1]⁺

Example50:5-Isopropyl-N-(1-methyl-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyridin-2-amine

5-Isopropyl-2-isothiocyanato-4-(trifluoromethyl)pyridine

To a mixture of thiophosgene (4 g, 35.26 mmol, 2.70 mL) in DCM (100 mL)was added a mixture of 5-isopropyl-4-(trifluoromethyl) pyridin-2-amine(3.6 g, 17.63 mmol) in DCM (30 mL) at 0° C. The mixture was stirred at0° C. for 2 h. The residue was cooled at 0° C. The mixture was addedsaturated sodium bicarbonate and the aqueous phase was extracted withDCM. The combined organic layers were dried over sodium sulfate,filtered and concentrated under reduced pressure to give a residue. Theresidue was purified by silica gel chromatography to give5-isopropyl-N-(1-methyl-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyridin-2-amine(3 g, 12.18 mmol, 69.10% yield).

5-Isopropyl-N-(1-methyl-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyridin-2-amine

To a mixture of 5-isopropyl-2-isothiocyanato-4-(trifluoromethyl)pyridine(2 g, 8.12 mmol) in DCM (20 mL) was added ammonium hydroxide (3.42 g,24.37 mmol, 3.75 mL, 25% purity). The mixture was stirred at 25° C. for1 h. The residue was concentrated in vacuum. The mixture was dilutedwith H₂O. The aqueous phase was extracted with EtOAc. The organic phasewas dried with anhydrous sodium sulfate and filtered. The filtrate wasconcentrated under vacuum to givemethyl(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)carbamimidothioate (2g, crude).

Methyl (5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)carbamimidothioate

To a mixture of [5-isopropyl-4-(trifluoromethyl)-2-pyridyl]thiourea (2g, crude) in ACN (20 mL) was added iodomethane (1.40 g, 9.86 mmol). Themixture was stirred at 70° C. for 1 h. and was concentrated. The residuewas diluted with H₂O. The aqueous phase was adjusted to pH=8 withsaturated sodium bicarbonate. The aqueous phase was extracted with EtOAcand the combined organic phases were dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by column chromatography followed by lyophilization to give1-[5-isopropyl-4-(trifluoromethyl)-2-pyridyl]-2-methyl-isothiourea (2 g,7.21 mmol).

Tert-Butyl 2-methyl-2-picolinoylhydrazinecarboxylate

To a mixture of pyridine-2-carboxylic acid (1.5 g, 12.18 mmol) andtert-butyl N-(methylamino)carbamate (1.78 g, 12.18 mmol) in DCM (60 mL)was added DIPEA (4.72 g, 36.55 mmol, 6.37 mL), hydroxybenzo (1.98 g,14.62 mmol) and carbodiimide (2.80 g, 14.62 mmol). The mixture wasstirred at 25° C. for 3 h. The mixture was diluted with DCM (30 mL),washed with aqueous hydrochloric acid (1 M, 40 mL) and H₂O. The organicphase was dried over sodium sulfate and filtered. The filtrate wasconcentrated under vacuum to give a crude product. The crude product waspurified by silica gel chromatography to give tert-butylN-[methyl(pyridine-2-carbonyl)amino]carbamate (2.2 g, 8.76 mmol, 71.86%yield).

N-Methylpicolinohydrazide hydrochloride

To a mixture of tert-butyl N-[methyl(pyridine-2-carbonyl)amino]carbamate(1 g, 3.98 mmol) in EtOAc (20 mL) was added EtOAc hydrochloric acid (4M,20 mL). The mixture was stirred at 25° C. for 2 h. The mixture wasfiltered and the filter cake concentrated to give the crude product. Thecrude product was triturated with EtOAc (20 mL) to giveN-methylpyridine-2-carbohydrazide (580 mg, 3.84 mmol, 96.41% yield).

N-Methylpicolinohydrazide

To a mixture of N-methylpyridine-2-carbohydrazide (1 g, 5.33 mmol, HCl)in MeOH (15 mL) was added Amberlyst A-26 (2 g). The mixture was stirredat 25° C. for 30 min. The mixture was filtered and the filtrate wasconcentrated. The residue was purified by silica gel chromatography togive N-methylpyridine-2-carbohydrazide (550 mg, 3.64 mmol, 68.27%yield).

5-Isopropyl-N-(1-methyl-5-(pyridin-2-yl)-1H-1,2,4-triazol-3-yl)-4-(trifluoromethyl)pyridin-2-amine

To a mixture of1-[5-isopropyl-4-(trifluoromethyl)-2-pyridyl]-2-methyl-isothiourea(750.47 mg, 2.71 mmol) in pyridine (8 mL) was addedN-methylpyridine-2-carbohydrazide (450 mg, 2.98 mmol). The mixture wasstirred at 120° C. for 3 h and then at 25° C. for 16 h. The mixture wasfiltered and the filtrate was concentrated. The product was isolated andpurified by standard methods to give5-isopropyl-N-[1-methyl-5-(2-pyridyl)-1,2,4-triazol-3-yl]-4-(trifluoromethyl)pyridin-2-amine(187.98 mg, 4.467 mmol, 17.25% yield). LCMS (ESI): m/z 363.1 [M+1]⁺.

Example 51:2-((3-(4-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylpyridine-3-sulfonamide

4-Isopropoxypicolinonitrile

To a solution of propan-2-ol (1.21 g, 20.21 mmol, 1.55 mL) in DMF (10mL) was added NaH (866.01 mg, 21.65 mmol, 60% purity) at 0° C. Themixture was stirred at 25° C. for 30 min then to the mixture was added4-chloropicolinonitrile (2 g, 14.43 mmol) in DMF (40 mL) at 0° C. Themixture was stirred at 25° C. for 1 h. The mixture was poured into coldsaturated NH₄Cl and then extracted with EtOAc. The combined organiclayers were washed with brine, dried with anhydrous sodium sulfate andfiltered. The filtrate was concentrated under reduced pressure and theresidue was purified by flash silica gel chromatography to give4-isopropoxypicolinonitrile (1.01 g, 6.23 mmol, 43.14% yield). LCMS(ESI): m/z 163.1 [M+1]⁺. ¹H NMR (400 MHz, CDCl₃) 8.48 (d, J=5.8 Hz, 1H),7.17 (d, J=2.4 Hz, 1H), 6.95 (dd, J₁=5.8, J₂=2.6 Hz, 1H), 4.70-4.63 (m,1H), 1.40 (d, J=6.1 Hz, 6H).

4-Isopropoxypicolinimidamide

To a solution of 4-isopropoxypicolinonitrile (1.01 g, 6.23 mmol) in MeOH(15 mL) was added sodium (71.58 mg, 3.11 mmol). The mixture was stirredat 25° C. for 12 h. To the mixture was added NH₄Cl (499.66 mg, 9.34mmol) and the mixture was stirred at 70° C. for 1.5 h. The reactionmixture was concentrated to give a residue which was triturated withMTBE:EtOAc (1:1, 10 mL) for 10 min, filtered and the filter cake wascollected and concentrated under reduced pressure to give4-isopropoxypicolinimidamide (1.4 g, crude, hydrochloride). LCMS (ESI):m/z 180.1 [M+1]⁺.

N-((3-(N,N-Dimethylsulfamoyl)pyridin-2-yl)carbamothioyl)-4-isopropoxypicolinimidamide

To a solution of 4-isopropoxypicolinimidamide (190 mg, crude,hydrochloride) and 2-isothiocyanato-N,N-dimethylpyridine-3-sulfonamide(214.34 mg, 0.88 mmol) in DCM (15 mL) and acetone (15 mL) was added TEA(445.71 mg, 4.40 mmol, 0.6 mL). The mixture was stirred at 25° C. for 12h. The mixture was concentrated to giveN-((3-(N,N-dimethylsulfamoyl)pyridin-2-yl)carbamothioyl)-4-isopropoxypicolinimidamide(372 mg, crude). LCMS (ESI): m/z 423.1 [M+1]⁺.

2-((3-(4-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylpyridine-3-sulfonamide

To a solution ofN-((3-(N,N-dimethylsulfamoyl)pyridin-2-yl)carbamothioyl)-4-isopropoxypicolinimidamide(372 mg, crude) in EtOH (10 mL) was added iodine (44.69 mg, 0.17 mmol)and hydrogen peroxide (199.65 mg, 1.76 mmol, 30% purity) at 0° C. Themixture was stirred at 25° C. for 1 h. The mixture was quenched byaddition of saturated sodium sulfite at 0° C. and the mixture wasconcentrated. The aqueous residue was extracted with EtOAc and thecombined organic phase was washed with brine, dried with anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by prep-HPLC (basic condition; column: Waters Xbridge BEH C18250*50 mm*10 um; mobile phase: [H₂O (0.04% NH₃H2O+10 mM NH₄HCO3)-ACN]; B%: 45%-75%, 8 min) to give2-((3-(4-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylpyridine-3-sulfonamide(200.82 mg, 0.472 mmol, 53.43% yield, 99% purity). ¹H NMR (400 MHz,DMSO-d₆) 10.67 (br s, 1H), 8.80 (dd, J=1.4, 4.8 Hz, 1H), 8.47 (d, J=5.6Hz, 1H), 8.28 (dd, J=1.5, 7.8 Hz, 1H), 7.69 (d, J=2.4 Hz, 1H), 7.38 (brdd, J=5.0, 7.5 Hz, 1H), 7.06 (dd, J=2.5, 5.8 Hz, 1H), 4.90-4.81 (m, 1H),2.80 (s, 6H), 1.33 (d, J=6.0 Hz, 6H). LCMS (ESI): m/z 421.2 [M+1]⁺.

Example 52:N-(2-((3-(4-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

Tert-Butyl(2-(3-(imino(4-isopropoxypyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of 4-isopropoxypicolinimidamide (241.95 mg, 1.35 mmol) andtert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.45 g, 1.35 mmol) in DCM (20 mL) and acetone (20 mL) was added TEA(683.04 mg, 6.75 mmol), then the mixture was stirred at 35° C. for 16 h.The mixture was combined with a previous batch (80 mg, crude) to givetert-butyl(2-(3-(imino(4-isopropoxypyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(770 mg, crude).

tert-Butyl(2-((3-(4-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(2-(3-(imino(4-isopropoxypyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(770 mg, crude) in EtOH (20 mL) was added iodine (761.43 mg, 3.00 mmol)at 0° C. and the mixture was stirred at 25° C. for 1 h. The mixture wasquenched by addition of saturated sodium sulfite at 0° C. The mixturewas concentrated and the aqueous residue was extracted with DCM and thecombined organic phase was washed with brine, dried with anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography to give tert-butyl(2-((3-(4-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.72 g, 1.41 mmol, 94.02% yield).

N²-(3-(4-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine

To a solution of tert-butyl tert-butyl(2-((3-(4-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.72 g, 1.41 mmol) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL)and the mixture was stirred at 20° C. for 1 h. The mixture wasconcentrated under vacuum to giveN²-(3-(4-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(0.6 g, 1.34 mmol, 95.2% yield, HCl).

N-(2-((3-(4-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a solution ofN²-(3-(4-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(0.45 g, 1.01 mmol, HCl) and TEA (509.49 mg, 5.03 mmol) in DMF (35 mL)was added Ac₂O (154.20 mg, 1.51 mmol) and the mixture was stirred at 35°C. for 16 h. Additional Ac₂O (102.80 mg, 1.01 mmol) was added to themixture and stirred at 40° C. for 6 h. Temperature was increased to 45°C. for 38 h and then the mixture was concentrated. The residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [H₂O (0.1% TFA)-ACN]; B %: 30%-50%, 10 min), followed bylyophilization to giveN-(2-((3-(4-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide(193.68 mg, 0.407 mmol, 40.38% yield, 95% purity). LCMS (ESI): m/z 453.3[M+1]+.

Example 53:N-(2-((3-(4-Methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

4-Methoxypicolinimidamide

To a solution of 4-methoxypicolinonitrile (1 g, 7.46 mmol) in MeOH (15mL) was added sodium methoxide (120.82 mg, 2.24 mmol) and the mixturewas stirred at 30° C. for 4 h. Then NH₄Cl (518.41 mg, 9.69 mmol) wasadded to the mixture and stirred at 75° C. for 2 h. The mixture wasconcentrated under vacuum and the residue was triturated with EtOAc andstirred for 0.5 h. The suspension was filtered and the filter cake wascollected. The filter cake was dissolved with H₂O and ACN followed byaddition of Amberlyst A-26(OH) (2 g) and the mixture was stirred at 25°C. for 30 min. The mixture was filtered through a pad of celite,concentrated under vacuum and then dried by lyophilization to give4-methoxypicolinimidamide (1.1 g, 7.28 mmol, 97.61% yield).

Tert-Butyl(2-(3-(imino(4-methoxypyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of 4-methoxypicolinimidamide (226.75 mg, 1.50 mmol) andtert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (0.5g, 1.50 mmol) in DCM (40 mL) and acetone (40 mL) was added TEA (758.94mg, 7.50 mmol, 1.04 mL) and the mixture was stirred at 35° C. for 16 h.The mixture was concentrated under vacuum to give tert-butyl(2-(3-(imino(4-methoxypyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(730 mg, crude).

Tert-Butyl(2-((3-(4-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(2-(3-(imino(4-methoxypyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(730 mg, crude) in EtOH (20 mL) was added iodine (761.43 mg, 3.00 mmol)at 0° C. and the mixture was stirred at 25° C. for 1 h. The mixture wasquenched by addition of saturated sodium sulfite at 0° C. and themixture was concentrated. The aqueous phase was extracted with DCM andthe combined organic phases were washed with brine, dried with anhydroussodium sulfate, filtered, and concentrated in vacuum. The residue waspurified by silica gel chromatography to givetert-butyl(2-((3-(4-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.5 g, 1.04 mmol).

N²-(3-(4-Methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine

To a solution of tert-butyl(2-((3-(4-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.5 g, 1.04 mmol) in EtOAc (20 mL) was added HCl/EtOAc (4 M, 20 mL) andthe mixture was stirred at 20° C. for 1 h. The temperature was increasedto 50° C. for 0.5 h and then concentrated under vacuum to giveN²-(3-(4-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(0.4 g, crude, HCl).

N-(2-((3-(4-Methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a solution ofN²-(3-(4-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(0.4 g, crude, HCl) and TEA (96.64 mg, 0.96 mmol) in DMF (30 mL) wasadded Ac₂O (146.25 mg, 1.43 mmol) and the mixture was stirred at 45° C.for 16 h. Additional Ac₂O (97.50 mg, 0.96 mmol) was added to the mixtureand it was stirred at 45° C. for 16 h. Additional Ac₂O (50 mg, 0.5 mmol)was added to the mixture and stirred at 40° C. for 64 h. The mixture wasconcentrated and the residue was triturated with MeOH. The resultingsuspension was filtered and the filter cake was dried by lyophilizationto giveN-(2-((3-(4-methoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide(166.26 mg, 0.385 mmol, 40.40% yield, 98.5% purity). LCMS (ESI): m/z425.1 [M+1]⁺.

Example 54:2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylpyridine-3-sulfonamide

2-Chloro-N,N-dimethylpyridine-3-sulfonamide

To a solution of 2-chloropyridine-3-sulfonyl chloride (10.2 g, 48.10mmol) in THE (100 mL) was added dimethylamine (2 M, 24.05 mL) dropwiseat 0° C. The mixture was stirred at 15° C. for 2 h. The mixture waspoured into ice-H₂O and the aqueous phase was extracted with EtOAc. Thecombined organic phase was washed with brine, dried with anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography to give2-chloro-N,N-dimethylpyridine-3-sulfonamide (6.6 g, 29.61 mmol, 61.56%yield, 99% purity).

2-Amino-N,N-dimethylpyridine-3-sulfonamide

This reaction was paralleled for three batches: A mixture of2-chloro-N,N-dimethylpyridine-3-sulfonamide (2 g, 9.06 mmol, 1 eq) andammonium hydroxide (19.06 g, 135.95 mmol, 20.94 mL) was stirred at 80°C. for 72 h in a sealed tube. The mixture was filtered and the filtercake was collected and dried under vacuum to give2-amino-N,N-dimethylpyridine-3-sulfonamide (5 g, 24.85 mmol, 91.38%yield).

2-Isothiocyanato-N,N-dimethylpyridine-3-sulfonamide

To a solution of thiophosgene (2.29 g, 19.88 mmol, 1.52 mL) in DCM (20mL) was added a solution of 2-amino-N,N-dimethylpyridine-3-sulfonamide(2 g, 9.94 mmol) in DCM (30 mL) and the mixture was stirred at 0° C. for2 h. The mixture was poured into saturated sodium bicarbonate at 0° C.and the aqueous phase was extracted with DCM. The combined organic phasewas concentrated under vacuum and the residue was purified by silica gelchromatography to give2-isothiocyanato-N,N-dimethylpyridine-3-sulfonamide (1.1 g, 4.52 mmol,45.48% yield).

N-((3-(N,N-Dimethylsulfamoyl)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide

To a solution of 2-isothiocyanato-N,N-dimethylpyridine-3-sulfonamide(0.3 g, 1.23 mmol) and 5-isopropoxypicolinimidamide (221 mg, 1.23 mmol)in DCM (20 mL) and acetone (20 mL) was added TEA (124.77 mg, 1.23 mmol)and the mixture was stirred at 35° C. for 16 h. The mixture was combinedwith another batch (0.2 g, crude) to giveN-((3-(N,N-dimethylsulfamoyl)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide(0.7 g, crude).

2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylpyridine-3-sulfonamide

To a solution of1-[3-(dimethylsulfamoyl)-2-pyridyl]-3-(5-isopropoxypyridine-2-carboximidoyl)thiourea(0.7 g, crude) in EtOH (30 mL) was added iodine (84.10 mg, 0.33 mmol)and hydrogen peroxide (375.68 mg, 3.31 mmol, 30% purity) at 0° C. Themixture was stirred at 20° C. for 1 h and then quenched by addition ofsaturated sodium sulfite at 0° C. The aqueous phase was extracted withDCM and the combined organic phase was dried with anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The mixture wastriturated with MeOH, the suspension was filtered and the filter cakewas dried by lyophilization to give2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethylpyridine-3-sulfonamide(322.18 mg, 0.76 mmol, 45.72% yield, 98.87% purity). LCMS (ESI): m/z421.2 [M+1]+.

Example 55:N-Methyl-N-(2-((3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)acetamide

Tert-Butyl (2-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

This reaction was paralleled for two batches: To a solution of sodiumazide (9.42 g, 144.83 mmol) (120 mL) was added tert-butyl(2-chloro-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (15 g, 48.28mmol), and the mixture was stirred at 100° C. for 16 h. The two batcheswere combined and poured into saturated sodium bicarbonate at 0° C. andstirred for 3 min. The aqueous phase was extracted with EtOAc and thecombined organic phase was washed with brine, and concentrated undervacuum to give tert-butyl(2-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (30 g,crude).

Tert-Butyl (2-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(2-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (30 g, crude)in MeOH (300 mL) was added Pd/C (3 g, 10% purity) and hydroxide Pd/C (3g, 20% purity) under nitrogen and the mixture was then stirred at 25° C.for 3 h under hydrogen (15 psi). The mixture was filtered through a padof celite and to the filtrate was added Pd/C (2 g, 10% purity) andhydroxide Pd/C (2 g, 20% purity), and stirred at 25° C. under hydrogen(15 psi) for 16 h. The mixture was filtered through a pad of Celite,washed with EtOAc, concentrated under vacuum and purified by silica gelchromatography to give tert-butyl(2-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (26 g, 89.26mmol, 94.40% yield).

Tert-Butyl (2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)Carbamate

To a solution of thiophosgene (4.79 g, 41.63 mmol, 3.19 mL) in DCM (20mL) was added a solution of tert-butyl(2-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (6 g, 20.60mmol) in DCM (50 mL) dropwise at 0° C. The mixture was stirred at 0° C.for 2 h. poured into saturated sodium bicarbonate at 0° C. and theaqueous phase was extracted with DCM. The combined organic phase wasconcentrated under vacuum and purified by silica gel chromatography togive tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl) carbamate(3.2 g, 9.60 mmol, 46.60% yield).

Picolinimidamide

To a solution of picolinonitrile (2 g, 19.21 mmol) in MeOH (15 mL) wasadded sodium methoxide (518.91 mg, 9.61 mmol) (freshly prepared), themixture was stirred at 30° C. for 4 h. NH₄Cl (1.34 g, 24.97 mmol) wasadded to the mixture and stirred at 75° C. for 2 h. The mixture wasconcentrated under vacuum and the residue was triturated with petroleumether:EtOAc (1:1, 20 mL) and stirred for 0.5 h. The resulting suspensionwas filtered and the filter cake was collected. The residue wasdissolved with H₂O and ACN followed by addition of Amberlyst A-26(OH) (2g) and stirred at 25° C. for 30 min. The mixture was filtered through apad of celite and the filtrate was concentrated under vacuum and thendried by lyophilization to give picolinimidamide (2.7 g, crude).

Tert-Butyl(2-(3-(imino(pyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (0.5g, 1.50 mmol) and picolinimidamide (181.71 mg, crude) in DCM (40 mL) andacetone (40 mL) was added TEA (758.93 mg, 7.50 mmol, 1.04 mL), themixture was stirred at 35° C. for 16 h. The mixture was concentratedunder vacuum to givetert-butyl(2-(3-(imino(pyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.86 g, crude).

Tert-Butylmethyl(2-((3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)carbamate

To a solution oftert-butyl(2-(3-(imino(pyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.86 g, crude) in EtOH (20 mL) was added iodine (960.57 mg, 3.78 mmol)at 0° C. and the mixture was stirred at 25° C. for 1 h. The mixture wasquenched by addition of saturated sodium sulfite at 0° C., concentratedand extracted with DCM. The combined organic phase was washed withbrine, dried with anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by silica gel chromatography togivetert-butylmethyl(2-((3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)carbamate(0.78 g, 1.72 mmol, 91.10% yield).

N³-Methyl-N²-(3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-2,3-diamine

To a solution oftert-butylmethyl(2-((3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)carbamate(0.78 g, 1.72 mmol) in EtOAc (20 mL) was added hydrochloric acid/EtOAc(4 M, 20 mL) and the mixture was stirred at 25° C. for 2 h. The mixturewas concentrated under vacuum to giveN³-methyl-N²-(3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-2,3-diamine,HCl salt (0.7 g, crude).

N-Methyl-N-(2-((3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)acetamide

To a solution ofN³-methyl-N²-(3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-2,3-diamine(0.55 g, crude, HCl salt) and TEA (789.79 mg, 7.80 mmol, 1.09 mL) in DMF(35 mL) was added Ac₂O (239.04 mg, 2.34 mmol) and the mixture wasstirred at 30° C. for 16 h. Additional Ac₂O (79.63 mg, 0.78 mmol) wasadded to the mixture and stirred at 30° C. for 16 h. The mixture wasconcentrated and purified by prep-HPLC (column: Phenomenex luna C18150*40 mm*15 um; mobile phase: [H₂O (0.225% FA)-ACN]; B %: 23%-53%, 8.5min) followed by lyophilization to giveN-methyl-N-(2-((3-(pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)acetamide(172.36 mg, 0.440 mmol, 27.90% yield, 99.6% purity). LCMS (ESI): m/z395.2 [M+1]+.

Example 56: Isopropyl2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino) Nicotinate

2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinicAcid

To a solution of methyl2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinate(0.3 g, 0.81 mmol) in MeOH (20 mL) and TH (10 mL) was added lithiumhydrate monohydrate (50.84 mg, 1.21 mmol) in H₂O (20 mL) and the mixturewas stirred at 25° C. for 3 h. The mixture was concentrated under vacuumto remove the volatiles and the residue was adjusted pH to 3-4 with HCland dried by lyophilization to give2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinicacid (370 mg, crude).

Isopropyl 2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)Nicotinate

To a solution of2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinicacid (370 mg, crude) in isopropanol (10 mL) and DMF (0.1 mL) was addedthionyl chloride (247.46 mg, 2.08 mmol) and the mixture was stirred at80° C. for 16 h. Additional thionyl chloride (492.00 mg, 4.14 mmol) wasadded to the mixture and stirred at 80° C. for 48 h. Additional thionylchloride (0.5 mL) along with a drop of DMF were added to the mixture andstirred at 80° C. for 16 h. The mixture was concentrated under vacuumand the residue was purified by prep-HPLC (column Waters Xbridge C18150*50 mm*10 um; mobile phase: [H₂O (0.05% ammonia hydroxide v/v)-ACN];B %: 50%-80%, 11.5 min), followed by lyophilization to give isopropyl2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino) nicotinate(104.65 mg, 0.262 mmol, 25.16% yield, 99.9% purity). LCMS (ESI): m/z400.2 [M+1]⁺.

Example 57:(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone

3-Bromo-5-(trifluoromethyl)pyridin-2-amine

To a solution of 5-(trifluoromethyl)pyridin-2-amine (10 g, 61.69 mmol)in THE (100 mL) was added NBS (11.53 g, 64.77 mmol) portionwise at 0° C.and the mixture was stirred at 20° C. for 1 h. The mixture wasconcentrated under vacuum and purified by silica gel columnchromatography to give 3-bromo-5-(trifluoromethyl)pyridin-2-amine (14 g,58.09 mmol, 94.17% yield).

Methyl 2-amino-5-(trifluoromethyl)nicotinate

To a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine (14 g, 58.09mmol), (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (904.26 mg,1.45 mmol) and TEA (17.63 g, 174.27 mmol, 24.26 mL) in MeOH (140 mL) wasadded [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.13g, 2.90 mmol). The mixture was de-gassed with nitrogen 3 times andstirred at 70° C. under carbon monoxide (50 psi) for 16 h. The mixturewas filtered through a pad of celite and the filtrate was concentratedunder vacuum. The residue was purified by silica gel chromatography togive methyl 2-amino-5-(trifluoromethyl)pyridine-3-carboxylate (12 g,52.33 mmol, 90.08% yield, 96% purity).

2-Amino-5-(trifluoromethyl) Nicotinic Acid

To a solution of methyl2-amino-5-(trifluoromethyl)pyridine-3-carboxylate (4 g, 18.17 mmol) inMeOH (40 mL) was added a solution of lithium hydroxide monohydrate (1.14g, 27.25 mmol) in H₂O (10 mL). The mixture was stirred at 25° C. for 5h, concentrated to remove the volatiles and the residue was adjusted pHto 5-6 with hydrochloric acid and dried by lyophilization to give2-amino-5-(trifluoromethyl) pyridine-3-carboxylic acid (5.5 g, crude).

(2-Amino-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone

To a mixture of 2-amino-5-(trifluoromethyl)pyridine-3-carboxylic acid(5.5 g, crude) and pyrrolidine (3.80 g, 53.37 mmol, 4.45 mL) in DMF (50mL) was added HATU (13.19 g, 34.69 mmol) and diisopropylethylamine(13.79 g, 106.73 mmol, 18.59 mL) at 0° C. and the mixture was stirred at25° C. for 22 h. To the mixture was added H₂O and EtOAc. The aqueousphase was extracted with EtOAc and the combined organic phase was washedwith brine, concentrated under vacuum, and purified by silica gel columnchromatography to give[2-amino-5-(trifluoromethyl)-3-pyridyl]-pyrrolidin-1-yl-methanone (5.4g, 20.83 mmol, 78.07% yield).

(2-Isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone

To a solution of thiocarbonyl dichloride (1.77 g, 15.43 mmol, 1.18 mL)in DCM (20 mL) was added a solution of[2-amino-5-(trifluoromethyl)-3-pyridyl]-pyrrolidin-1-yl-methanone (2 g,7.72 mmol) in DCM (30 mL) dropwise at 0° C., and the mixture was stirredat 0° C. for 2 h. The mixture was poured into saturated sodiumbicarbonate and the aqueous phase was extracted with DCM. The combinedorganic phase was concentrated under vacuum and purified by silica gelcolumn chromatography to give[2-isothiocyanato-5-(trifluoromethyl)-3-pyridyl]-pyrrolidin-1-yl-methanone(0.86 g, 2.71 mmol, 35.15% yield, 95% purity).

5-Isopropoxy-N-((3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide

To a solution of[2-isothiocyanato-5-(trifluoromethyl)-3-pyridyl]-pyrrolidin-1-yl-methanone(0.86 g, 2.71 mmol) and 5-isopropoxypyridine-2-carboxamidine (511.56 mg,2.85 mmol) in DCM (50 mL) and acetone (50 mL) was added TEA (1.44 g,14.23 mmol, 1.99 mL) and the mixture was stirred at 30° C. for 16 h. Themixture was concentrated under vacuum to give1-(5-isopropoxypyridine-2-carboximidoyl)-3-[3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)-2-pyridyl]thiourea(1.37 g, crude).

(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(pyrrolidin-1-yl)methanone

To a solution of1-(5-isopropoxypyridine-2-carboximidoyl)-3-[3-(pyrrolidine-1-carbonyl)-5-(trifluoromethyl)-2-pyridyl]thiourea(1.37 g, crude) in EtOH (20 mL) was added iodine (1.45 g, 5.70 mmol) at0° C. and the mixture was stirred at 25° C. for 1 h. The mixture wasquenched by addition of saturated sodium sulfite aqueous at 0° C. andconcentrated. The aqueous phase was extracted with DCM and the combinedorganic phase was washed with brine, dried with anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The residue waspurified by prep-HPLC (column: Phenomenex Synergi C18 150*25*10 um;mobile phase: [H₂O (0.2% FA)-ACN]; B %: 50%-80%, 11 min) followed bylyophilization to give[2-[[3-(5-isopropoxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-pyrrolidin-1-yl-methanone(448.51 mg, 936.41 umol, 32.84% yield, 99.9% purity). LCMS (ESI): m/z479.1 [M+1]+.

Example 58:N-Methyl-n-(2-((3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)acetamide

5-(Oxetan-3-yloxy)picolinonitrile

To a solution of NaH (1.97 g, 49.14 mmol, 60% purity) in DMF (25 mL) wasadded oxetan-3-ol (2.37 g, 31.94 mmol) at 0° C. and the mixture wasstirred for 0.5 h. To the mixture was added a solution of5-fluoropicolinonitrile (3 g, 24.57 mmol) in DMF (15 mL) at 0° C. andstirred at 0° C. for 0.5 h. The reaction mixture was poured intosaturated NH₄Cl at 0° C. and the aqueous phase was extracted with EtOAc.The combined organic phase was washed with brine, dried with anhydroussodium sulfate, filtered, and concentrated under vacuum. The residue waspurified by silica gel chromatography to give5-(oxetan-3-yloxy)picolinonitrile (4 g, 22.71 mmol, 92.41% yield).

5-(Oxetan-3-yloxy)picolinimidamide

To a solution of 5-(oxetan-3-yloxy)picolinonitrile (4 g, 22.71 mmol) inMeOH (30 mL) was added sodium methoxide (613.31 mg, 11.35 mmol, fresh)and the mixture was stirred at 35° C. for 4 h. NH₄Cl (1.58 g, 29.52mmol) was added to the mixture and stirred at 75° C. for 2 h. Themixture was concentrated under vacuum, triturated with petroleumether:EtOAc (1:1) and stirred for 0.5 h. The suspension was filtered,and the filter cake was collected and dissolved in H₂O and ACN followedby addition of Amberlyst A-26(OH) (2 g). The mixture was stirred at 25°C. for 0.5 h and filtered through a pad of celite. The filtrate wasconcentrated under vacuum, then dried by lyophilization to give5-(oxetan-3-yloxy)picolinimidamide (4.6 g, crude).

Tert-Butyl(2-(3-(imino(5-(oxetan-3-yloxy)pyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of 5-(oxetan-3-yloxy)picolinimidamide (260.83 mg, 1.35mmol) and tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.45 g, 1.35 mmol) in DCM (50 mL) and acetone (50 mL) was added TEA(683.04 mg, 6.75 mmol) and the mixture was stirred at 30° C. for 16 h.The mixture was concentrated under vacuum to give tert-butyl(2-(3-(imino(5-(oxetan-3-yloxy)pyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.7 g, crude).

Tert-Butylmethyl(2-((3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)carbamate

To a solution of tert-butyl(2-(3-(imino(5-(oxetan-3-yloxy)pyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.7 g, crude) in EtOH (30 mL) was added hydrogen peroxide (301.47 mg,2.66 mmol, 30% purity) and iodine (67.49 mg, 0.26 mmol) at 0° C. and themixture was stirred at 20° C. for 1 h. The mixture was quenched byaddition of saturated sodium sulfite aqueous at 0° C. and the aqueousphase was extracted with EtOAc. The combined organic phase was washedwith brine, dried with anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gelchromatography to give tert-butylmethyl(2-((3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)carbamate(480 mg, 0.92 mmol, 68.83% yield).

N³-Methyl-N²-(3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-2,3-diamine

To a solution of tert-butylmethyl(2-((3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)carbamate(0.48 g, 0.92 mmol) in DCM (20 mL) was added trifluoroacetic acid (7.70g, 67.53 mmol, 5 mL) at 0° C., then the mixture was stirred at 20° C.for 3 h. The mixture was concentrated under vacuum below 35° C. Theresidue was diluted with DCM and poured into sodium bicarbonate at 0° C.The aqueous phase was extracted with DCM and the combined organic phasewas dried with anhydrous sodium sulfate, filtered, and concentratedunder vacuum to giveN³-methyl-N²-(3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-2,3-diamine(0.4 g, crude).

N-Methyl-N-(2-((3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)acetamide

To a solution ofN³-methyl-N²-(3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)-5-(trifluoromethyl)pyridine-2,3-diamine(0.4 g, crude) and TEA (476.86 mg, 4.71 mmol) in DMF (35 mL) was addedAc₂O (144.33 mg, 1.41 mmol) and the mixture was stirred at 45° C. for 16h. The mixture was concentrated and the residue was purified byprep-HPLC (column: Phenomenex Synergi C18 150*25*10 um; mobile phase:[H₂O (0.2% FA)-ACN]; B %: 32%-62%, 11 min) followed by lyophilization togiveN-methyl-N-(2-((3-(5-(oxetan-3-yloxy)pyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)acetamide(168.99 mg, 0.350 mmol, 37.48% yield, 97.5% purity). LCMS (ESI): m/z467.1 [M+1]⁺.

Example 59:N-(5-(difluoromethyl)-2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide

Tert-Butyl(5-(difluoromethyl)-2-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(5-(difluoromethyl)-2-isothiocyanatopyridin-3-yl)(methyl)carbamate (0.4g, 1.27 mmol) and1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide (223.53mg, 1.27 mmol) in DCM (10 mL) and acetone (10 mL) was added TEA (641.79mg, 6.34 mmol). The mixture was stirred at 30° C. for 16 h undernitrogen. The mixture was concentrated under vacuum to givetert-butyl(5-(difluoromethyl)-2-(3-(imino(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.62 g, crude).

Tert-Butyl(5-(difluoromethyl)-2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(5-(difluoromethyl)-2-(3-(imino(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyridin-3-yl)(methyl)carbamate(0.62 g, crude) in EtOH (10 mL) was added iodine (640.26 mg, 2.52 mmol)at 0° C. The mixture was stirred at 15° C. for 15 min and then quenchedwith saturated sodium sulfite at 0° C. The mixture was concentrated, theaqueous phase was diluted with H₂O and extracted with EtOAc. Thecombined organic phase was dried with anhydrous sodium sulfate, filteredand concentrated. The residue was purified by flash silica gelchromatography to give tert-butyl(5-(difluoromethyl)-2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate(0.55 g, 1.06 mmol, 83.73% yield, 94% purity).

5-(Difluoromethyl)-N3-methyl-N2-(3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diaminehydrochloride

To a solution of tert-butyl(5-(difluoromethyl)-2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)(methyl)carbamate(0.55 g, 1.06 mmol) in EtOAc (5 mL) was added hydrochloride/EtOAc (4 M,10 mL) at 0° C. The mixture was stirred at 30° C. for 0.5 h and thenconcentrated under vacuum.5-(difluoromethyl)-N3-methyl-N2-(3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine,HCl salt (0.45 g, crude).

N-(5-(Difluoromethyl)-2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide

To a solution of5-(difluoromethyl)-N3-methyl-N2-(3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diamine(0.45 g, crude, hydrochloride) and Ac₂O (140.23 mg, 1.37 mmol) in ACN(20 mL) was added TEA (534.60 mg, 5.28 mmol). The mixture was stirred at35° C. for 32 h. The mixture was concentrated under vacuum and theresidue was purified by prep-HPLC (column: Phenomenex Luna C18 200*40mm*10 um; mobile phase: [H₂O (0.225% FA)-ACN]; B %: 5%-35%, 8.5 min)followed by lyophilization to giveN-(5-(difluoromethyl)-2-((3-(1-methyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)-N-methylacetamide(263.37 mg, 0.780 mmol, 54.88% yield, 95% purity). LCMS (ESI): m/z 432.3[M+1]⁺.

Example 60:N-[2-[[3-(3,3-Dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-acetamide

3,3-Dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridine-5-carboxamidine

To a solution of3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile (500. mg,2.67 mmol) in MeOH (10 mL) was added a solution of Na (18.43 mg, 0.8000mmol) in MeOH (3 mL) and the mixture was stirred at 30° C. for 16 h. Themixture was concentrated under vacuum and the residue was trituratedwith EtOAc and stirred for 0.5 h. The suspension was filtered and thefiltrate was concentrated under vacuum to recover3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile. The filtercake was suspended in H₂O and ACN with OH-type resin and stirred for 0.5h. The mixture was filtered through a pad of celite and filtrate wasdried by lyophilization to give3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridine-5-carboxamidine (50 mg,0.2448 mmol, 9.2% yield).

3,3-Dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile

To a solution of 5-chloro-3,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-2-one(650. mg, 3.31 mmol) in DMA (10 mL) were added zinc cyanide (766.26 mg,6.61 mmol) and tetrakis[triphenylphosphine]palladium(0) (191. mg, 0.1700mmol), the mixture was stirred at 120° C. for 16 h under nitrogen. Themixture was filtered through a pad of celite and the filtrate was pouredinto H₂O. The aqueous phase was extracted with EtOAc and the combinedorganic phase was washed with brine, dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum. The residue waspurified by flash silica gel chromatography to give3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile (180 mg,0.9615 mmol, 29.1% yield). LCMS (ESI): m/z 188.1 [M+1]+.

Tert-ButylN-[2-isothiocyanato-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate

To a solution of thiocarbonyl dichloride (3.66 mL, 48.07 mmol) in DCM(30 mL) was added a solution of tert-butylN-[2-amino-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate (7.0 g,24.03 mmol) in DCM (50 mL) at 0° C. and the mixture was stirred at 0° C.for 2 h. The mixture was poured into saturated sodium bicarbonate andthe aqueous phase was extracted with DCM. The combined organic phase wasconcentrated under vacuum and purified by silica gel chromatography togive tert-butylN-[2-isothiocyanato-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate(3.4 g, 10.2 mmol, 42.4% yield).

Tert-ButylN-[6-[(4-isopropoxypyridine-2-carboximidoyl)carbamothioylamino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate

To a solution of tert-butylN-[6-isothiocyanato-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate(500. mg, 1.5 mmol) and 4-isopropoxypyridine-2-carboxamidine (538.52 mg,3 mmol) in DCM (20 mL) and acetone (20 mL) was added TEA (1.15 mL, 4.5mmol) and the mixture was stirred at 35° C. for 16 h. The mixture wasconcentrated under vacuum to give crude tert-butylN-[6-[(4-isopropoxypyridine-2-carboximidoyl)carbamothioylamino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate(770 mg, 1.5023 mmol, 100.15% yield). LCMS (ESI): m/z 512.9 [M+1]+.

N-[2-[[3-(3,3-Dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-acetamide

To a solution of3,3-dimethyl-5-[5-[[3-(methylamino)-5-(trifluoromethyl)-2-pyridyl]amino]-1,2,4-thiadiazol-3-yl]-1H-pyrrolo[2,3-c]pyridin-2-one;hydrochloride(160. mg, 0.3400 mmol) and TEA (0.02 mL, 0.3400 mmol) in DMF (5 mL) wasadded acetyl acetate (103.84 mg, 1.02 mmol) and the mixture was stirredat 30° C. for 16 h. The mixture was concentrated and the residue wasresuspended in THE (5 mL). To this was added sodium hydroxide (2 M, 5mL) and the mixture was stirred at 25° C. for 1 h. The mixture wasconcentrated under vacuum and purified by prep-HPLC (column: PhenomenexGemini-NX C18 75*30 mm*3 um; mobile phase: [H₂O (0.1% TFA)-ACN]; B %:35%-45%, 10 min), then dried by lyophilization to giveN-[2-[[3-(3,3-dimethyl-2-oxo-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl]amino]-5-(trifluoromethyl)-3-pyridyl]-N-methyl-acetamide(56.46 mg, 0.1126 mmol, 33.2% yield). LCMS (ESI): m/z 478.1 [M+1]+

Example 61:N-Methyl-N-(5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamide

tert-Butyl(2-(3-(imino(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide(530. mg, 2.43 mmol) and tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(809.42 mg, 2.43 mmol) in DCM (5 mL) and acetone (5 mL) was added TEA(3.1 mL, 12.14 mmol) and the mixture was stirred at 25° C. for 16 h. Themixture was concentrated under vacuum to give tert-butyl(2-(3-(imino(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.34 g, crude). LCMS (ESI): m/z 552.1 [M+1]⁺.

Tert-Butylmethyl(5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate

To a solution oftert-butyl(2-(3-(imino(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.34 g, crude) in EtOH (20 mL) was added iodine (123.32 mg, 0.4900mmol) and hydrogen peroxide (550.82 mg, 4.86 mmol, 30% purity) at 0° C.The mixture was stirred at 25° C. for 0.5 h, quenched with saturatedsodium sulfite aqueous, and the mixture was concentrated under vacuum.The mixture was extracted with EtOAc and the combined organic phase waswashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under vacuum. The residue was purified by flash silica gelchromatography to give tert-butylmethyl(5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(330 mg, 0.4744 mmol, 19.5% yield). LCLCMS (ESI): m/z 550.0 [M+1]⁺.

1,3,3-Trimethyl-5-(5-((3-(methylamino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-2(3H)-one

To a solution of tert-butylmethyl(5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(300 mg, 0.5500 mmol) in EtOAc (10 mL) was added hydrochloric acid/EtOAc(10 mL, 40 mmol) and the mixture was stirred at 20° C. for 2 h. Themixture was concentrated under vacuum to give1,3,3-trimethyl-5-(5-((3-(methylamino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-2(3H)-one;hydrochloride (260 mg, 0.5351 mmol, 98.021% yield).

N-Methyl-N-(5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamide

To a solution of1,3,3-trimethyl-5-(5-((3-(methylamino)-5-(trifluoromethyl)pyridin-2-yl)amino)-1,2,4-thiadiazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-2(3H)-one;hydrochloride (260. mg, 0.5400 mmol) and TEA (0.68 mL, 2.68 mmol) in DMF(15 mL) was added acetyl acetate (109.25 mg, 1.07 mmol). The mixture wasstirred at 40° C. for 16 h. Additional acetyl acetate (0.05 mL, 0.5400mmol) was added to the mixture and stirred at 40° C. for 6 h. Themixture was concentrated and the residue was purified by prep-HPLC(column: Unisil 3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [H₂O(0.225% FA)-ACN]; B %: 45%-65%, 10 min), then dried by lyophilization togiveN-methyl-N-[5-(trifluoromethyl)-2-[[3-(1,3,3-trimethyl-2-oxo-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl]amino]-3-pyridyl]acetamide(106.58 mg, 0.2134 mmol, 39.9% yield). LCMS (ESI): m/z 492.1 [M+1]⁺.

Example 62:N-Methyl-N-(5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamide

Tert-Butyl(2-(3-(imino(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamidehydrochloride (200. mg, 0.8300 mmol) and tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(415.4 mg, 1.25 mmol) in DCM (10 mL) and acetone (10 mL) was added TEA(420.35 mg, 4.15 mmol). The mixture was stirred at 25° C. for 6 h undernitrogen and then concentrated under vacuum to givetert-butyl(2-(3-(imino(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(600 mg, crude). LCMS (ESI): m/z 538 [M+1]⁺.

Tert-Butylmethyl(5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate

To a mixture of tert-butyl(2-(3-(imino(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(600 mg, crude) in EtOH (20 mL) was added iodine (424.91 mg, 1.67 mmol)at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture wascooled and poured into saturated sodium sulfite. The mixture wasconcentrated and the aqueous phase was extracted with EtOAc. Thecombined organic phase was dried over anhydrous sodium sulfate, filteredand concentrated under vacuum. The residue was purified by flash silicagel chromatography to give tert-butylmethyl(5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(300 mg, 0.5433 mmol, 48.7% yield). LCMS (ESI): 536 [M+1]⁺.

N3-Methyl-5-(trifluoromethyl)-N2-(3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diaminehydrochloride

To a mixture of tert-butylmethyl(5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)carbamate(300. mg, 0.5400 mmol) in EtOAc (4 mL) was added hydrogen chloride/EtOAc(4.07 mL, 16.3 mmol). The mixture was stirred at 25° C. for 1 h. Themixture was concentrated under vacuum to giveN₃-methyl-5-(trifluoromethyl)-N2-(3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diaminehydrochloride (250 mg, 0.5297 mmol, 97.499% yield). LCMS (ESI): m/z 436[M+1]⁺.

N-Methyl-N-(5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamide

To a mixture ofN3-methyl-5-(trifluoromethyl)-N2-(3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)pyridine-2,3-diaminehydrochloride (250 mg, 0.5300 mmol) and TEA (160.81 mg, 1.59 mmol) inDMF (3 mL) was added acetyl acetate (81.12 mg, 0.7900 mmol). The mixturewas stirred at 40° C. for 16 h and then concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Phenomenex Luna C18 150*25mm*10 um; mobile phase: [H₂O (0.225% FA)-ACN]; B %: 19%-49%, 10 min)followed by lyophilization to giveN-methyl-N-(5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyridin-3-yl)acetamide(110.93 mg, 0.2263 mmol, 42.7% yield). LCMS (ESI): m/z 478.2 [M+1]⁺.

Example 63:2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethyl-5-(trifluoromethyl)pyridine-3-sulfonamide

3-Bromo-5-(trifluoromethyl)pyridin-2-amine

To a solution of 5-(trifluoromethyl)pyridin-2-amine (20 g, 123.37 mmol,1 eq) in ACN (200 mL) was added 1-bromopyrrolidine-2,5-dione (26.35 g,148.05 mmol) in portions at 0° C. The mixture was stirred at 25° C. for2 h. The mixture was concentrated under vacuum and the residue waspurified by silica gel chromatography to give3-bromo-5-(trifluoromethyl)pyridin-2-amine (27 g, 107.55 mmol, 87.17%yield, 96% purity).

3-Bromo-2-isothiocyanato-5-(trifluoromethyl)pyridine

To a solution of thiocarbonyl dichloride (9.54 g, 82.98 mmol) in DCM (30mL) was added a solution of 3-bromo-5-(trifluoromethyl)pyridin-2-amine(10. g, 41.49 mmol) in DCM (50 mL) dropwise at 0° C. and the mixture wasstirred at 25° C. for 16 h. The mixture was poured into saturated sodiumbicarbonate and the aqueous phase was extracted with DCM. The combinedorganic phase was concentrated under vacuum and purified by silica gelchromatography to give3-bromo-2-isothiocyanato-5-(trifluoromethyl)pyridine (3 g, 10.598 mmol,25.5% yield). LCMS (ESI): m/z 285.2 [M+1]⁺.

N-((3-Bromo-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide

To a solution of 3-bromo-2-isothiocyanato-5-(trifluoromethyl)pyridine(1.6 g, 5.65 mmol) and 5-isopropoxypyridine-2-carboxamidine (1.01 g,5.65 mmol) in DCM (20 mL) and acetone (20 mL) was added TEA (0.79 mL,5.65 mmol) and the mixture was stirred at 25° C. for 16 h. The mixturewas concentrated under vacuum to give crudeN-((3-bromo-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide(2.6 g, crude).

N-(3-Bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution of crudeN-((3-bromo-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide(2.6 g, crude) in EtOH (10 mL) was added iodine (175.68 mg, 0.69 mmol)and hydrogen peroxide (784.5 mg, 6.92 mmol, 30% purity) at 0° C. Themixture was stirred at 25° C. for 0.5 h. The mixture was quenched byaddition of saturated sodium sulfite aqueous at 0° C. and concentratedunder vacuum. The aqueous phase was extracted with EtOAc and thecombined organic phase was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by flash silica gel chromatography to giveN-(3-bromo-5-(trifluoromethyl)pyridin-2-yl)-3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-amine(1 g, 2.1726 mmol, 38.6% yield). LCMS (ESI): m/z 459.9 [M+1]⁺.

3-(5-Isopropoxypyridin-2-yl)-N-(3-((4-methoxybenzyl)thio)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine

To a solution ofN-((3-bromo-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)-5-isopropoxypicolinimidamide(1 g, 2.17 mmol) and (4-methoxyphenyl)methanethiol (502.63 mg, 3.26mmol) in 1,4-dioxane (10 mL) was addedtris(dibenzylideneacetone)dipalladium(0) (99.48 mg, 0.1100 mmol),N-ethyl-N-isopropylpropan-2-amine (561.58 mg, 4.35 mmol) and(5-diphenylphosphinyl-9,9-dimethylxanthen-4-yl)-diphenylphosphine (62.86mg, 0.1100 mmol). The mixture was de-gassed with nitrogen 3 times andstirred at 100° C. for 16 h under nitrogen. The mixture was filteredthrough a pad of celite and the filtrate was concentrated under vacuum.The residue was purified by flash silica gel chromatography to give3-(5-isopropoxypyridin-2-yl)-N-(3-((4-methoxybenzyl)thio)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(1 g, 1.8741 mmol, 86.3% yield). LCMS (ESI): m/z 534.2 [M+1]⁺.

2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridine-3-sulfonicacid

To a solution of3-(5-isopropoxypyridin-2-yl)-N-(3-((4-methoxybenzyl)thio)-5-(trifluoromethyl)pyridin-2-yl)-1,2,4-thiadiazol-5-amine(900 mg, 1.69 mmol) in a mixture of DCM (10.5 mL), acetic acid (1.5 mL)and H₂O (3 mL) was added a solution of1,3-dichloro-5,5-dimethylhydantoin (660.84 mg, 3.37 mmol) in DCM (5 mL)at 0° C. The mixture was stirred at 0° C. for 2 h and then poured intoH₂O. The aqueous phase was extracted with DCM and the combined organicphase was dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was collected to give2-[[3-(5-isopropoxy-2-pyridyl)-1,2,4-thiadiazol-5-yl]amino]-5-(trifluoromethyl)pyridine-3-sulfonicacid (1 g, crude). LCMS (ESI): m/z 462.0 [M+1]⁺.

2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridine-3-sulfonylchloride

To a solution of2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridine-3-sulfonicacid (700. mg, 1.52 mmol) in phosphorus oxychloride (10 mL, 110.28 mmol)was added phosphorus pentachloride (631.8 mg, 3.03 mmol) and the mixturewas stirred at 60° C. for 3 h. The mixture was diluted with DCM, pouredinto saturated sodium bicarbonate aqueous, then adjusted pH to 7-8 withsodium bicarbonate solid at 0° C. The aqueous phase was extracted withDCM and the combined organic phase was washed with brine, dried overanhydrous sodium sulfate, and filtered to give2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridine-3-sulfonylchloride (730 mg, crude).

2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethyl-5-(trifluoromethyl)pyridine-3-sulfonamide

To a solution of crude2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridine-3-sulfonylchloride (730. mg, crude) in DCM (50 mL) was added dimethylamine (1.52mL, 3.04 mmol) (2 M in THF) and the mixture was stirred at 25° C. for 2h. The mixture was concentrated under vacuum. The residue was trituratedwith MeOH and DMF at 60° C. for 16 h. The filter cake was dried bylyophilization, then dried by centrifuge. All the mother liquid wascombined and purified by prep-HPLC (column: Phenomenex Gemini-NX C1875*30 mm*3 um; mobile phase: H₂O (0.1% TFA)-ACN]; B %: 55%-65%, 10 min),then dried by lyophilization. The two part product was combined anddried by lyophilization to give2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-N,N-dimethyl-5-(trifluoromethyl)pyridine-3-sulfonamide(178.38 mg, 0.3619 mmol, 23.788% yield). LCMS (ESI): m/z 489.1 [M+1]⁺.

Example 64:N,N-Dimethyl-5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

5-Chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one

To a mixture of NaH (3.56 g, 88.98 mmol) in DMF (30 mL) was added asolution of 5-chloro-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (3. g, 17.8mmol) in DMF (20 mL) at 0° C. The mixture was stirred at 25° C. for 0.5h then iodomethane (12.63 g, 88.98 mmol) was added at 0° C. The mixturewas stirred at 25° C. for 2 h. The mixture was cooled and poured intoice H₂O slowly. The aqueous phase was extracted with EtOAc and thecombined organic phase was washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by flash silica gel chromatography to give5-chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (3.5 g,16.614 mmol, 93.4% yield).

5-Chloro-1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine

To a solution of5-chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (2. g, 9.49mmol) in THE (10 mL) was added borane in THE (47.47 mL, 47.47 mmol), themixture was stirred at 60° C. for 16 h. Then additional borane in THE(18.99 mL, 18.99 mmol) was added to the mixture and stirred at 60° C.for 20 h. The mixture was cooled and poured into cold H₂O and the pH wasadjusted to 5-6 with hydrochloric acid. The aqueous phase was extractedwith EtOAc and the combined organic phase was washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by flash silica gel chromatography to give5-chloro-1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine (1.3 g,6.6097 mmol, 69.6% yield). LCMS (ESI): m/z 197.1 [M+1]⁺.

1,3,3-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile

To a solution of5-chloro-1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine (1.2 g,6.1 mmol) in DMF (15 mL) was addedtetrakis[triphenylphosphine]palladium(0) (352.52 mg, 0.3100 mmol) andzinc cyanide (1.41 g, 12.2 mmol) and the mixture was stirred at 120° C.for 16 h. The mixture was filtered through a pad of celite and thefiltrate was poured into H₂O. The aqueous phase was extracted with EtOAcand the combined organic phase was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by flash silica gel chromatography to give1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile(300 mg, 1.6022 mmol, 26.26% yield). LCMS (ESI): m/z 188.1 [M+1]+.

1,3,3-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide

To a solution of1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile(0.3 g, 1.6 mmol) in MeOH (5 mL) was added a solution of sodium (11.06mg, 0.4800 mmol) in MeOH (5 mL) and the mixture was stirred at 25° C.for 16 h. Then NH₄Cl (129.78 mg, 2.4 mmol) was added to the mixture andstirred at 75° C. for 2 h. The mixture was concentrated under vacuum andto the residue was added MTBE (10 mL) and stirred at 25° C. for 1 h. Thesuspension was filtered and to the filter cake in H₂O and ACN was addedOH-type resin (1 g). The mixture was stirred for 1 h and filteredthrough a pad of celite. The filtrate was dried under lyophilization togive1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide(160 mg, 0.7833 mmol, 48.887% yield). LCMS (ESI): m/z 205.1 [M+1]⁺.

2-(3-(Imino(1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-N,N-dimethyl-5-(trifluoromethyl)nicotinamide

To a solution of1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide(90. mg, 0.4400 mmol) and2-isothiocyanato-N,N-dimethyl-5-(trifluoromethyl)nicotinamide (121.27mg, 0.4400 mmol) in DCM (5 mL) and acetone (5 mL) was added TEA (0.56mL, 2.2 mmol) and the mixture was stirred at 25° C. for 1 h undernitrogen. Then2-isothiocyanato-N,N-dimethyl-5-(trifluoromethyl)nicotinamide (60 mg,0.22 mmol) was added to the mixture and stirred at 25° C. for 16 h. Themixture was concentrated under vacuum to give2-(3-(imino(1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-N,N-dimethyl-5-(trifluoromethyl)nicotinamide(210 mg, crude).

N,N-Dimethyl-5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

To a solution of crude2-(3-(imino(1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-N,N-dimethyl-5-(trifluoromethyl)nicotinamide(210. mg, crude) in EtOH (10 mL) was added iodine (222.31 mg, 0.8800mmol) at 0° C. and the mixture was stirred at 25° C. for 1 h. To themixture was added saturated sodium sulfite at 0° C. and the mixture wasconcentrated under vacuum. The aqueous phase was extracted with EtOAcand the combined organic phase was washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated under vacuum. Theresidue was purified by prep-HPLC (column: Unisil 3-100 C18 Ultra 150*50mm*3 um; mobile phase: [H₂O (0.225% FA)-ACN]; B %: 30%-50%, 10 min),then dried by lyophilization to giveN,N-dimethyl-5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide(47.78 mg, 0.0990 mmol, 22.6% yield, formic acid). LCMS (ESI): m/z 478.2[M+1]⁺.

Example 65:N,N-Dimethyl-5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

1,3,3-Trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile

To a solution of5-chloro-1,3,3-trimethyl-1H-pyrrolo[2,3-c]pyridin-2(3H)-one (2.7 g,12.82 mmol) and tetrakis[triphenylphosphine]palladium(0) (1.48 g, 1.28mmol) in DMF (20 mL) was added zinc cyanide (2.97 g, 25.63 mmol) undernitrogen and the mixture was stirred at 120° C. for 16 h. The mixturewas filtered through a pad of Celite and the filtrate was poured intoH₂O. The aqueous phase was extracted with EtOAc and the combined organicphase was washed with brine, dried over anhydrous sodium sulfate,filtered and concentrated under vacuum. The filter cake was quenchedwith hydrochloric acid (1 M, 200 mL) and discarded. The residue waspurified by flash silica gel chromatography to give1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile(0.3000 g, 1.4909 mmol, 11.6% yield).

1,3,3-Trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide

To a solution of1,3,3-trimethyl-2-oxo-2,3-dihydro-H-pyrrolo[2,3-c]pyridine-5-carbonitrile(300. mg, 1.49 mmol) in MeOH (3 mL) was added sodium methoxide (0.04 mL,0.7500 mmol) and the mixture was stirred at 25° C. for 16 h. Then NH₄Cl(120.76 mg, 2.24 mmol) was added to the mixture and stirred at 75° C.for 2 h. The mixture was concentrated under vacuum and the residue wastriturated with MTBE and stirred at 25° C. for 0.5 h. The suspension wasfiltered and the filter cake was dried under vacuum to give1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide(170 mg, 0.7789 mmol, 52.243% yield). LCMS (ESI): m/z 219.1 [M+1]+.

N,N-Dimethyl-5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

To a solution of1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide(40 mg, 0.1800 mmol) and2-isothiocyanato-N,N-dimethyl-5-(trifluoromethyl)nicotinamide (151.33mg, 0.5500 mmol) in DCM (10 mL) and acetone (10 mL) was added TEA (92.66mg, 0.9200 mmol), the mixture was stirred at 25° C. for 24 h. Themixture was concentrated under vacuum and purified by prep-HPLC (column:Phenomenex Synergi C18 150*25*10 um; mobile phase: [H₂O (0.225%FA)-ACN]; B %: 35%-65%, 10 min) followed by lyophilization to giveN,N-dimethyl-5-(trifluoromethyl)-2-((3-(1,3,3-trimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide(23.74 mg, 0.0475 mmol, 25.9% yield). LCMS (ESI): m/z 492.2 [M+1]⁺.

Example 66:N,N-Dimethyl-5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

N-(4-(2-Hydroxy-2-methylpropyl)pyridin-3-yl)pivalamide

To a solution of N-(4-methylpyridin-3-yl)pivalamide (7.5 g, 39.01 mmol)in THE (100 mL) was added dropwise n-butyllithium (34.33 mL, 85.82 mmol,2.5 M in THF) at −70° C. Upon complete addition, the mixture was stirredat 0° C. for 1 hr. Acetone (4.52 g, 78.02 mmol, 5.74 mL) was addeddropwise at −70° C. The mixture was stirred at 20° C. for 16 hr,quenched by addition of H₂O at 0° C. and extracted with EtOAc. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by flash silica gel chromatography to giveN-(4-(2-hydroxy-2-methylpropyl)pyridin-3-yl)pivalamide (9 g, 35.95 mmol,75.00% yield). LCMS (ESI): m/z 251.2 [M+1]⁺.

2,2-Dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine

A mixture of N-(4-(2-hydroxy-2-methylpropyl)pyridin-3-yl)pivalamide (9g, 35.95 mmol) and hydrochloric acid (12 M, 30 mL) in H₂O (30 mL) wasdegassed and purged with nitrogen 3 times and then the mixture wasstirred at 80° C. for 36 h under nitrogen. The reaction mixture wasconcentrated under reduced pressure, purified by prep-HPLC (column:Waters Xbridge BEH C18 250*50 mm*10 um; mobile phase: [H₂O (0.05%ammonia hydroxide v/v)-ACN]; B %: 15%-38%, 20 min) and followed bylyophilization to give2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine (4 g, 26.99 mmol,75.07% yield). LCMS (ESI): m/z 149.2 [M+1]⁺.

Tert-Butyl2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of 2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine (3.5g, 23.62 mmol) and 4-(dimethylamino)pyridine (12.98 g, 106.27 mmol) inACN (10 mL) was added a solution of tert-butoxy carbonyl tert-butylcarbonate (20.62 g, 94.46 mmol, 21.70 mL) in ACN (10 mL). The mixturewas stirred at 20° C. for 16 h under nitrogen, concentrated underreduced pressure and purified by flash silica gel chromatography to givetert-butyl2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (2.1 g,8.03 mmol, 34.02% yield, 95% purity). LCMS (ESI): m/z 249.0 [M+1]⁺.

1-(tert-Butoxycarbonyl)-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine6-oxide

To a solution of tert-butyl2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate (1.50g, 6.03 mmol) in DCM (20 mL) was added m-CPBA (2606.07 mg, 12.09 mmol,80% purity) and the mixture was stirred at 25° C. for 1 hour. Themixture was concentrated under reduced pressure and purified by silicagel chromatography to give1-(tert-butoxycarbonyl)-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine6-oxide (1.70 g, 5.48 mmol, 96.05% yield). LCMS (ESI): m/z 265.2 [M+1]⁺.

tert-Butyl-5-cyano-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate

To a solution of1-(tert-butoxycarbonyl)-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine 6-oxide (2.0 g, 7.57 mmol) in ACN (20 mL) was added TEA (2.0mL, 14.35 mmol) followed by trimethylsilylformonitrile (5.35 g, 52.97mmol). The mixture was stirred at 80° C. for 16 h and then concentratedunder reduced pressure. The residue was purified by columnchromatography to give tert-butyl5-cyano-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.1 g, 4.0244 mmol, 53.18% yield).

2,2-Dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile

To a mixture of tert-butyl5-cyano-2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-1-carboxylate(1.0 g, 3.66 mmol) in DCM (10 mL) was added trifluoroacetic acid (10 mL,134.19 mmol) at 0° C. The mixture was stirred at 0° C. for 2 h andconcentrated. The residue was poured into cold H₂O and the aqueous phaseadjusted to pH 8 with sodium carbonate. The mixture was extracted withEtOAc and the combined organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated under vacuum to give2,2-dimethyl-1,3-dihydropyrrolo[2,3-c]pyridine-5-carbonitrile (700 mg,crude). LCLCMS (ESI): m/z 174 [M+1]⁺.

1,2,2-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile

To a mixture of2,2-dimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile (0.7g, crude) in DMF (10 mL) was added NaH (0.32 g, 8.08 mmol) at 0° C. Themixture was stirred at 20° C. for 0.5 h. Then iodomethane (0.57 g, 4.04mmol) was added and the mixture was stirred at 20° C. for 1 h. Themixture was cooled and poured into ice H₂O. The aqueous phase wasextracted with EtOAc and the combined organic phase was washed withbrine, dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum. The residue was purified by flash silica gelchromatography to give1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile(500 mg, 2.617 mmol, 64.8% yield).

1,2,2-Trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamidehydrochloride

Sodium (18.43 mg, 0.8000 mmol) was added to MeOH (5 mL) and to thissolution was added1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbonitrile(500. mg, 2.67 mmol). The mixture was stirred at 30° C. for 16 h. NH₄Cl(185.69 mg, 3.47 mmol) was added and the mixture was stirred at 70° C.for 1 h. The mixture was concentrated and the residue was trituratedwith petroleum ether:EtOAc (1:1) to give1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamidehydrochloride (500 mg, 2.077 mmol, 77.78% yield).

2-(3-(Imino(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-N,N-dimethyl-5-(trifluoromethyl)nicotinamide

To a mixture of1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamidehydrochloride (250. mg, 1.04 mmol) and2-isothiocyanato-N,N-dimethyl-5-(trifluoromethyl)nicotinamide (285.85mg, 1.04 mmol) in DCM (10 mL) and acetone (10 mL) was added TEA (525.43mg, 5.19 mmol). The mixture was stirred at 25° C. for 16 h undernitrogen. The mixture was concentrated under vacuum to giveN,N-dimethyl-5-(trifluoromethyl)-2-[(1,2,2-trimethyl-3H-pyrrolo[2,3-c]pyridine-5-carboximidoyl)carbamothioylamino]pyridine-3-carboxamide(500 mg, crude).

N,N-Dimethyl-5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide

To a mixture of2-(3-(imino(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-N,N-dimethyl-5-(trifluoromethyl)nicotinamide(500 mg, crude) in EtOH (20 mL) was added iodine (396.98 mg, 1.56 mmol)at 0° C. The mixture was stirred at 25° C. for 1 h. The mixture wascooled and poured into saturated sodium sulfite, concentrated and theaqueous phase extracted with EtOAc. The combined organic phase was driedover anhydrous sodium sulfate, filtered and concentrated under vacuum.The residue was purified by prep-HPLC (column: Phenomenex luna C18150*40 mm*15 um; mobile phase: [H₂O (0.225% FA)-ACN]; B %: 19%-49%, 10min) to give the crude product. The crude product was purified byprep-HPLC (column: Phenomenex Gemini-NX C18 75*30 mm*3 um; mobile phase:[H₂O (0.1% FA)-ACN]; B %: 32%-42%, 7 min) to giveN,N-dimethyl-5-(trifluoromethyl)-2-((3-(1,2,2-trimethyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)nicotinamide(95.36 mg, 0.1945 mmol, 18.654% yield). LCMS(ESI): 478.2 [M+1]⁺.

Example 67:N-(6-((5-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

6-Chloro-5-(trifluoromethyl)pyridin-3-amine

To the solution of iron powder (11.71 g, 209.68 mmol) and NH₄Cl (22.43g, 419.35 mmol) in EtOH (250 mL) and H₂O (25 mL) was added2-chloro-5-nitro-3-(trifluoromethyl)pyridine (9.5 g, 41.94 mmol). Thereaction was stirred at 80° C. for 5 h. The reaction mixture wasfiltered and concentrated under reduced pressure. The residue wasdiluted with EtOAc, washed with H₂O, dried over anhydrous sodiumsulfate, concentrated under reduced pressure, and purified by silica gelcolumn chromatography to give6-chloro-5-(trifluoromethyl)pyridin-3-amine (5.41 g, 26.26 mmol, 62.61%yield). LCMS (ESI) m/z 197.0 [M+1]⁺.

Tert-Butyl (6-chloro-5-(trifluoromethyl)pyridin-3-yl)carbamate

To a solution of 6-chloro-5-(trifluoromethyl)pyridin-3-amine (5.41 g,26.26 mmol) and DMAP (320.78 mg, 2.63 mmol) in pyridine (30 mL) wasadded di-tert-butyl dicarbonate (7.45 g, 34.13 mmol, 7.84 mL) dropwise.The mixture was stirred at 30° C. for 15 h. The reaction mixture wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography to give tert-butyl(6-chloro-5-(trifluoromethyl)pyridin-3-yl)carbamate (5.72 g, 18.32 mmol,69.76% yield, 95% purity).

Tert-Butyl (6-chloro-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(6-chloro-5-(trifluoromethyl)pyridin-3-yl)carbamate (10.2 g, 34.38 mmol)in DMF (200 mL) was added NaH (2.06 g, 51.57 mmol, 60% purity) at 0° C.and the mixture was stirred at 0° C. for 0.5 h. Iodomethane (7.32 g,51.57 mmol, 3.21 mL) was then added to the reaction mixture at 0° C. Theresulting mixture was stirred at 30° C. for 2 h under nitrogenatmosphere. The mixture was poured into saturated NH₄Cl solution thenextracted with EtOAc. The organic layer was washed with brine, driedover anhydrous sodium sulfate, filtered and concentrated under reducedpressure to give methyl(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)carbamimidothioate (10 g,32.19 mmol, 93.61% yield).

Tert-Butyl (6-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of methyl(5-isopropyl-4-(trifluoromethyl)pyridin-2-yl)carbamimidothioate (450 mg,1.45 mmol) in DMSO (8 mL) was added sodium azide (282.47 mg, 4.35 mmol)at 25° C. and the mixture was stirred at 100° C. for 12 h under nitrogenatmosphere. The reaction mixture was poured into ice cold saturatedsodium bicarbonate and stirred for 3 min. The aqueous phase wasextracted with EtOAc and the combined organic phase was concentratedunder vacuum to give tert-butyl(6-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (440 mg,crude).

Tert-Butyl (6-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(6-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (420 mg,crude) in MeOH (5 mL) was added Pd/C (100 mg, 0.09 mmol, 10% purity)under nitrogen, then the mixture was degassed and purged with hydrogen 3times, and the mixture was stirred at 30° C. for 12 h under hydrogen (15psi) atmosphere. The mixture was filtered, and the filtrate wasconcentrated under reduced pressure and the residue purified by silicagel column chromatography to give tert-butyl(6-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (200 mg,51.87% yield).

Tert-Butyl (6-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)Carbamate

To a solution of thiophosgene (3.16 g, 27.47 mmol, 2.11 mL) in DCM (20mL) was added a solution of tert-butyl(6-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (4 g, 13.73mmol) in DCM (30 mL) dropwise at 0° C., then the mixture was stirred at0° C. for 2 h. The mixture was poured into saturated sodium bicarbonateat 0° C. The aqueous phase was extracted with DCM and the combinedorganic phase was concentrated under vacuum. The residue was purified bysilica gel chromatography to give tert-butyl(6-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl) carbamate(1.3 g, 3.90 mmol, 28.40% yield) and recovered tert-butyl(6-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (2.2 g, 7.55mmol, 55% yield).

Tert-Butyl methyl(6-thioureido-5-(trifluoromethyl)pyridin-3-yl)carbamate

To a solution of tert-butyl(6-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl) carbamate(1.3 g, 3.90 mmol) in DCM (10 mL) was added ammonium hydroxide (911.20mg, 7.80 mmol, 1.00 mL, 30% purity) dropwise at 25° C. and the mixturewas stirred at 25° C. for 1 h. The mixture was dried with anhydroussodium sulfate, filtered and concentrated under vacuum to givetert-butyl methyl(6-thioureido-5-(trifluoromethyl)pyridin-3-yl)carbamate(1.5 g, crude).

Tert-Butyl (6-((imino(methylthio)methyl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butylmethyl(6-thioureido-5-(trifluoromethyl)pyridin-3-yl)carbamate (1.5 g,crude) in ACN (10 mL) was added iodomethane (729.22 mg, 5.14 mmol) andthe mixture was stirred at 60° C. for 2 h. The mixture was concentratedunder vacuum and purified by flash silica gel chromatography to givetert-butyl(6-((imino(methylthio)methyl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(0.42 g, 1.15 mmol, 26.92% yield).

Tert-Butyl(6-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution oftert-butyl(6-((imino(methylthio)methyl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(300 mg, 0.82 mmol) and1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbohydrazide(181.35 mg, 0.82 mmol) in tertiary butanol (3 mL) was addedp-toluenesulfonic acid (47 mg, 0.25 mol) and the mixture was stirred at120° C. for 2 h under microwave irradiation. Additionalp-toluenesulfonic acid (31.32 mg, 0.16 mmol) was added to the mixtureand stirred at 120° C. for 2 h under microwave irradiation. The mixturewas concentrated under vacuum and purified by prep-HPLC (column: Unisil3-100 C18 Ultra 150*50 mm*3 um; mobile phase: [H₂O (0.225% FA)-ACN]; B%: 28%-58%, 10 min) followed by lyophilization to givetert-butyl(6-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(70 mg, 0.14 mmol, 16.40% yield).

N²-(5-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)-N-methyl-3-(trifluoromethyl)pyridine-2,5-diamine

To a solution of tert-butyl(6-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(70 mg, 0.14 mmol) in EtOAc (5 mL) was added hydrochloric acid/EtOAc (4M, 5 mL) and the mixture was stirred at 25° C. for 2 h. The mixture wasconcentrated under vacuum to giveN²-(5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)-N⁵-methyl-3-(trifluoromethyl)pyridine-2,5-diamine,HCl salt (60 mg, 0.13 mmol, 97.71% yield).

N-(6-((5-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a solution ofN²-(5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)-N⁵-methyl-3-(trifluoromethyl)pyridine-2,5-diamine(60 mg, 0.13 mmol, hydrochloric acid salt) and TEA (66.74 mg, 0.66 mmol)in DMF (2 mL) was added Ac₂O (40.40 mg, 0.40 mmol) and the mixture wasstirred at 40° C. for 19 h. Additional Ac₂O (20.20 mg, 0.20 mmol) wasadded to the mixture and stirred at 40° C. for 4 h followed by a drop oftrifluoroacetic acid, then concentrated under vacuum. The residue wasresuspended in THF:sodium hydroxide aqueous (6 M) (1:1) and stirred at25° C. for 2 h, then concentrated under vacuum. The residue was purifiedby prep-HPLC (column: Phenomenex luna C18 150*25 mm*10 um; mobile phase:[H₂O (0.225% FA)-ACN]; B %: 12%-42%, 10 min), then dried bylyophilization to giveN-(6-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide(21.89 mg, 0.045 mmol, 34.10% yield, 94.6% purity). ¹H NMR (400 MHz,DMSO-d₆) 9.31-9.21 (m, 1H), 8.37-8.34 (m, 1H), 8.14-8.00 (m, 1H),7.87-7.77 (m, 2H), 4.05-3.99 (m, 1H), 3.55-3.54 (m, 2H), 3.35 (s, 1H),3.13-3.12 (m, 4H), 2.20 (s, 0.7H), 1.80 (s, 2.3H), 1.16 (d, J=6.6 Hz,6H); LCMS (ESI) m/z 461.3 [M+1]⁺.

Example 68:N-(2-((5-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

Tert-ButylN-[2-isothiocyanato-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate

To a solution of thiophosgene (3.95 g, 34.33 mmol, 2.63 mL) in DCM (100mL) was added a solution of tert-butyl(2-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (5.0 g, 17.17mmol) in DCM (50 mL). The mixture was poured into saturated sodiumbicarbonate solution and extracted with DCM. The combined organic layerswere dried over sodium sulfate, filtered and concentrated under reducedpressure to give tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(5.50 g, crude). LCMS (ESI) m/z 334.0 [M+1]⁺.

Tert-ButylN-[2-(carbamothioylamino)-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate

To a solution of tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (5.5g, crude) in DCM (50 mL) was added ammonium hydroxide (6.94 g, 49.50mmol, 7.63 mL, 25% purity). The mixture was stirred at 30° C. for 1 h.The reaction mixture was concentrated under reduced pressure, pouredinto H₂O, extracted with EtOAc and the organic layer washed with brine,dried over sodium sulfate, filtered and concentrated under reducedpressure to give t tert-butylN-[2-(carbamothioylamino)-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate(5.78 g, crude). LCMS (ESI) m/z 351.1 [M+1]⁺.

Tert-ButylN-methyl-N-[2-[(methylsulfanylcarbonimidoyl)amino]-5-(trifluoromethyl)-3-pyridyl]carbamate

To a solution of tert-butylN-[2-(carbamothioylamino)-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate(5.78 g, crude) in ACN (50 mL) was added iodomethane (3.51 g, 24.75mmol, 1.54 mL). The mixture was stirred at 40° C. for 12 h. The mixturewas concentrated under vacuum and the residue was diluted with H₂O. Theaqueous phase was adjusted to pH 8 with saturated sodium bicarbonate.The aqueous phase was extracted with EtOAc and the combined organicphase was dried over anhydrous sodium sulfate, filtered and concentratedunder vacuum to give a residue. The residue was purified by silica gelcolumn chromatography to give tert-butylN-methyl-N-[2-[(methylsulfanylcarbonimidoyl)amino]-5-(trifluoromethyl)-3-pyridyl]carbamate(3.7 g, 10.15 mmol, 61.55% yield). ¹H NMR (400 MHz, CDCl₃) 8.40 (s, 1H),7.85-7.59 (m, 1H), 7.26 (s, 1H), 3.15 (s, 3H), 2.48 (s, 3H), 1.51 (s,2H), 1.30 (s, 7H).

tert-Butyl-(2-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butylN-methyl-N-[2-[(methylsulfanylcarbonimidoyl)amino]-5-(trifluoromethyl)-3-pyridyl]carbamate(827.13 mg, 2.27 mmol) and1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carbohydrazide (500mg, 2.27 mmol) in n-butyl alcohol (3 mL) was added p-toluenesulfonicacid (195.44 mg, 1.13 mmol). The mixture was stirred at 120° C. for 2 hunder microwave irradiation. Then additional p-toluenesulfonic acid(195.44 mg, 1.13 mmol) was added in the mixture and stirred at 120° C.for 2 h under microwave irradiation. The mixture was concentrated undervacuum and the residue was triturated with EtOAc. The suspension wasfiltered and the filtrate was purified by prep-HPLC (column: Phenomenexluna C18 150*40 mm*15 um; mobile phase: [H₂O (0.225% FA)-ACN]; B %:28%-58%, 9 min), then dried by lyophilization to givetert-butyl(2-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(242 mg, 0.47 mmol, 20.56% yield).

N²-(5-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine

To a solution oftert-butyl(2-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(240 mg, 0.46 mol) in EtOAc (10 mL) was added hydrochloric acid/EtOAc (4M, 10 mL) and the mixture was stirred at 25° C. for 2 h. The mixture wasconcentrated under vacuum and the residue was triturated with EtOAc andstirred for 1 h. The suspension was filtered and the filter cake wasconcentrated under vacuum to giveN²-(5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(200 mg, crude, hydrochloric acid).

N-(2-((5-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a solution ofN²-(5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(370 mg, 0.88 mmol, hydrochloride) and TEA (447.40 mg, 4.42 mmol, 0.6mL) in DMF (10 mL) was added Ac₂O (270.83 mg, 2.65 mmol, 0.25 mL) andthe mixture was stirred at 40° C. for 16 h. The mixture was concentratedunder vacuum and the crude product and another batch product (120 mg)were combined and purified by prep-HPLC (column: Waters Xbridge 150*25mm*5 um; mobile phase: [H₂O (0.05% ammonia hydroxide v/v)-ACN]; B %:31%-60%, 10 min), the eluent was combined with another batch of productand dried by lyophilzation to giveN-(2-((5-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1H-1,2,4-triazol-3-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide(166.51 mg, 0.358 mmol, 71.55% yield, 99% purity). 1H NMR (400 MHz,DMSO-d6) δ 8.46 (s, 1H), 8.22-7.92 (m, 1H), 7.82 (s, 1H), 7.67 (s, 1H),3.97-3.94 (m, 1H), 3.48-3.39 (m, 2H), 3.23 (s, 1H), 3.04 (s, 2H),3.03-2.94 (m, 2H), 2.18 (s, 1H), 1.78 (s, 2H), 1.15 (d, J=6.7 Hz, 6H).LCMS (ESI) m/z 461.3 [M+1]⁺.

Example 69:N-(6-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-methylpyridin-3-yl)-N-methylacetamide

Tert-Butyl (6-bromo-5-methylpyridin-3-yl)carbamate

This reaction was paralleled for two batches: To a solution of6-bromo-5-methylpyridin-3-amine (9.5 g, 50.79 mmol) and di-tert-butyldicarbonate (11.09 g, 50.79 mmol, 11.67 mL) in ACN (120 mL) was addedN,N-dimethylpyridin-4-amine (6.21 g, 50.79 mmol) and TEA (10.28 g,101.58 mmol, 14.14 mL). The mixture was stirred at 80° C. for 12 h. Twobatches of parallel reactions were combined. The mixture wasconcentrated and purified by flash silica gel chromatography to givetert-butyl (6-bromo-5-methylpyridin-3-yl)carbamate (22.3 g, crude).

Tert-Butyl (6-bromo-5-methylpyridin-3-yl)(methyl)carbamate

This reaction was paralleled for two batches: To a solution oftert-butyl (6-bromo-5-methylpyridin-3-yl)carbamate (7.75 g, crude) inDMF (100 mL) was added NaH (1.51 g, 37.78 mmol, 60% purity) at 0° C. andthe mixture was stirred at 25° C. for 0.5 h. Iodomethane (4.98 g, 35.09mmol, 2.18 mL) was added at 0° C. and the mixture was stirred at 25° C.for 1 h. Two batches of parallel reactions were combined, and themixture was diluted with cold saturated NH₄Cl and extracted with EtOAc.The combined organic layers were washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure and purified by column chromatography to give tert-butyl(6-bromo-5-methylpyridin-3-yl)(methyl)carbamate (20.4 g, crude). LCMS(ESI): m/z 301.0 [M+1]⁺.

Tert-Butyl(6-((ethoxycarbonyl)amino)-5-methylpyridin-3-yl)(methyl)carbamate

This reaction was paralleled for two batches: A mixture of tert-butyl(6-bromo-5-methylpyridin-3-yl)(methyl)carbamate (2.5 g, 8.30 mmol),ethyl carbamate (1.85 g, 20.75 mmol), sodium 2-methylpropan-2-olate (2M, 8.30 mL) in THE (50 mL) and the mixture was degassed and purged withnitrogen 3 times. To this mixture was added[2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium;dicyclohexyl-[3,6-dimethoxy-2-(2,4,6-triisopropylphenyl)phenyl]phosphane(376.23 mg, 0.42 mmol) and the mixture was stirred at 100° C. for 12 hunder nitrogen atmosphere. The two batches of parallel reactions werecombined, diluted with H₂O and extracted with EtOAc. The combinedorganic layers were washed with brine, dried over anhydrous sodiumsulfate and filtered. The filtrate was concentrated under reducedpressure and purified by flash silica gel chromatography to givetert-butyl(6-((ethoxycarbonyl)amino)-5-methylpyridin-3-yl)(methyl)carbamate (3.5g, crude). LCMS (ESI): m/z 310.1 [M+1]⁺.

Tert-Butyl (6-amino-5-methylpyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(6-((ethoxycarbonyl)amino)-5-methylpyridin-3-yl)(methyl) carbamate (3.85g, crude) in EtOH (40 mL) and H₂O (8 mL) was added lithium hydroxidehydrate (2.61 g, 62.23 mmol). The mixture was stirred at 90° C. for 2 h.The mixture was concentrated, H₂O was added to the mixture and theorganics were extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure and purified by flashsilica gel chromatography to give tert-butyl(6-amino-5-methylpyridin-3-yl)(methyl)carbamate (1.57 g, 6.62 mmol,53.16% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.83 (s, 1H), 7.24-7.19 (m,1H), 4.43-4.27 (m, 2H), 3.20 (s, 3H), 2.13 (s, 3H), 1.44 (s, 9H). LCMS(ESI): m/z 238.1 [M+1]⁺.

Tert-Butyl (6-isothiocyanato-5-methylpyridin-3-yl)(methyl)carbamate

To a solution of thiophosgene (1.99 g, 17.32 mmol, 1.33 mL) in DCM (20mL) was added tert-butyl (6-amino-5-methylpyridin-3-yl)(methyl)carbamate(1.37 g, 5.77 mmol) in DCM (15 mL) at 0° C. The mixture was stirred at25° C. for 12 h and then poured into saturated sodium bicarbonate at 0°C. The mixture was extracted with DCM, combined organic layers wereconcentrated under reduced pressure and purified by columnchromatography to give tert-butyl(6-isothiocyanato-5-methylpyridin-3-yl)(methyl)carbamate (1.08 g,crude). LCMS (ESI): m/z 280.1 [M+1]⁺.

Tert-Butyl(6-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)-5-methylpyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(6-isothiocyanato-5-methylpyridin-3-yl)(methyl)carbamate (857.31 mg,3.07 mmol) and 5-isopropoxypicolinimidamide (500 mg, 2.79 mmol) in DCM(50 mL) and acetone (50 mL) was added TEA (1.41 g, 13.95 mmol, 1.94 mL).The mixture was stirred at 25° C. for 12 h and concentrated to givetert-butyl (6-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)-5-methylpyridin-3-yl)(methyl)carbamate (1.28 g, crude). LCMS(ESI): m/z 459.2 [M+1]⁺.

Tert-Butyl(6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-methylpyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(6-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)-5-methylpyridin-3-yl)(methyl)carbamate (1.28 g, 2.79 mmol)in EtOH (20 mL) was added iodine (141.69 mg, 0.56 mmol) and hydrogenperoxide (632.96 mg, 5.58 mmol, 0.54 mL, 30% purity) at 0° C. Themixture was stirred at 25° C. for 40 min and then quenched by additionof saturated sodium sulfite at 0° C. The mixture was concentrated andthe aqueous phase extracted with EtOAc. The combined organic phase waswashed with brine, dried with anhydrous sodium sulfate, filtered andconcentrated to give the residue under vacuum. The residue wastriturated with petroleum ether:EtOAc (10:1, 50 mL) for 10 min,filtered, and the filter cake was collected and concentrated underreduced pressure to give tert-butyl(6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-methylpyridin-3-yl)(methyl)carbamate (855 mg, crude). LCMS(ESI): m/z 457.1 [M+1]⁺.

N²-(3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N⁵,3-dimethylpyridine-2,5-diamine

To a solution of tert-butyl(6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-methylpyridin-3-yl)(methyl)carbamate(805 mg, crude) in EtOAc (10 mL) was added hydrogen chloride/EtOAc (20mL, 4 M) and the mixture was stirred at 25° C. for 2 h. The mixture wasconcentrated to giveN²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N⁵,3-dimethylpyridine-2,5-diamine(692 mg, crude, hydrochloride). LCMS (ESI): m/z 357.1 [M+1]⁺.

N-(6-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-methylpyridin-3-yl)-N-methylacetamide

To a solution ofN²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N⁵,3-dimethylpyridine-2,5-diamine(692 mg, 1.76 mmol, hydrochloride) in DMF (15 mL) was added TEA (891.10mg, 8.81 mmol, 1.23 mL) and Ac₂O (233.74 mg, 2.29 mmol, 0.21 mL). Themixture was stirred at 40° C. for 12 h. The mixture was concentrated andpurified by prep-HPLC (column: Phenomenex Luna PFP(2) 150*21.2 mm 5u;mobile phase: [H₂O (0.2% FA)-ACN]; B %: 30%-60%, 10 min) to giveN-(6-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-methylpyridin-3-yl)-N-methylacetamide(249.2 mg, 0.621 mmol, 99.3% purity). ¹H NMR (400 MHz-DMSO d₆) δ 11.93(s, 1H), 8.34-8.33 (m, 2H), 8.17 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.52(dd, J₁=8.9, J₂=2.9 Hz, 1H), 4.82-4.76 (m, 1H), 3.15 (s, 3H), 2.42 (s,3H), 1.80 (s, 3H), 1.33 (d, J=6.0 Hz, 6H). LCMS (ESI): m/z 399.1 [M+1]⁺.

Example 70:N-(6-((3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

Tert-Butyl(6-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a solution of tert-butyl(6-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl) carbamate(452.01 mg, 1.36 mmol) and1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide (277mg, 1.36 mmol) in DCM (20 mL) and acetone (20 mL) was added TEA (686.09mg, 6.78 mmol, 0.94 mL). The mixture was stirred at 25° C. for 12 h andthe mixture was concentrated to give tert-butyl(6-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(729 mg, crude). LCMS (ESI): m/z 538.1 [M+1]⁺.

Tert-Butyl(6-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(6-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(729 mg, crude) in EtOH (15 mL) was added iodine (68.83 mg, 0.27 mmol)and hydrogen peroxide (307.50 mg, 2.71 mmol, 0.26 mL, 30% purity) at 0°C. and the mixture was stirred at 25° C. for 6 min. The mixture wasquenched by addition of saturated sodium sulfite at 0° C. and themixture was concentrated. The aqueous phase was extracted with EtOAc andthe combined organic phase was washed with brine, dried with anhydroussodium sulfate, filtered and concentrated under vacuum to givetert-butyl(6-((3-(1-isopropyl-2,3-dihydro-H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(770 mg, crude). LCMS (ESI): m/z 536.1 [M+1]⁺.

N²-(3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N-methyl-3-(trifluoromethyl)pyridine-2,5-diamine

A mixture of tert-butyl(6-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(770 mg, crude) in EtOAc (10 mL) was added hydrogen chloride/EtOAc (20mL, 4 M) and the resulting mixture was stirred at 25° C. for 1.5 h. Thereaction mixture was concentrated under vacuum to giveN²-(3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N⁵-methyl-3-(trifluoromethyl)pyridine-2,5-diamine(678 mg, crude, hydrochloride). LCMS (ESI): m/z 436.1 [M+1]⁺.

N-(6-((3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a mixture ofN²-(3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N⁵-methyl-3-(trifluoromethyl)pyridine-2,5-diamine(678 mg, crude, hydrochloride) in DMF (15 mL) was added Ac₂O (190.67 mg,1.87 mmol, 0.17 mL) and TEA (726.88 mg, 7.18 mmol, 1 mL) at 25° C. andthe mixture was stirred at 40° C. for 12 h. The reaction mixture wasfiltered and the filtrate was purified by prep-HPLC (column: Phenomenexluna C18 250*50 mm*10 um; mobile phase: [H₂O (0.05% HCl)-ACN]; B %:5%-35%, 10 min) to giveN-(6-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide(168.79 mg, 286.02 μmol, 22.51% yield, 87% purity, hydrochloride). ¹HNMR (400 MHz, DMSO-d₆) δ 8.86-8.77 (m, 1H), 8.42-8.26 (m, 1H), 8.12 (s,1H), 7.79 (s, 1H), 4.15-4.08 (m, 1H), 3.73-3.69 (m, 2H), 3.41 (s, 0.8H),3.33-3.29 (m, 2H), 3.19 (s, 2.2H), 2.24 (s, 0.8H), 1.84 (s, 2.2H), 1.18(d, J=6.5 Hz, 6H). LCMS (ESI): m/z 478.2 [M+1]⁺

Example 71:N-(2-((3-(4-Isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

Tert-Butyl (2-chloro-5-(trifluoromethyl)pyridin-3-yl)carbamate

This reaction was paralleled for two batches: To a solution of2-chloro-5-(trifluoromethyl) pyridin-3-amine (15 g, 76.31 mmol) in ACN(200 mL) was added TEA (15.44 g, 152.63 mmol, 21.24 mL) anddi-tert-butyl dicarbonate (16.66 g, 76.31 mmol, 17.53 mL) andN,N-dimethylpyridin-4-amine (9.32 g, 76.31 mmol) at 25° C. The mixturewas stirred at 80° C. for 12 h. The two batches of mixture was combinedand the mixture was concentrated under vacuum and purified by flashsilica gel chromatography to give tert-butyl(2-chloro-5-(trifluoromethyl)pyridin-3-yl)carbamate (34.9 g, crude).

Tert-Butyl (2-chloro-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

This reaction was paralleled for two batches: To a mixture of tert-butyl(2-chloro-5-(trifluoromethyl)pyridin-3-yl)carbamate (16.9 g, crude) inDMF (200 mL) was added NaH (3.19 g, 79.75 mmol, 60% purity) at 0° C. andthe mixture was stirred at 25° C. for 0.5 h. To the mixture was thenadded methyl iodide (10.51 g, 74.05 mmol, 4.61 mL) at 0° C. and it wasstirred at 25° C. for 1 h. The two batches were poured into coldsaturated NH₄Cl slowly and the aqueous phase was extracted with EtOAc.The combined organic phase was concentrated and purified by columnchromatography to give tert-butyl(2-chloro-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (39.9 g,64.21 mmol).

Tert-Butyl (2-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

This reaction was paralleled for two batches: To a mixture of tert-butyl(2-chloro-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (19.95 g,64.21 mmol) in DMSO (250 mL) was added sodium azide (12.52 g, 192.63mmol) at 25° C. and the mixture was stirred at 100° C. for 12 h. The twobatches were combined, poured into saturated sodium bicarbonate slowlyat 0° C. and stirred for 10 min. The aqueous phase was extracted withEtOAc and the combined organic phase was concentrated under vacuum togive tert-butyl(2-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (50 g,crude).

Tert-Butyl (2-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

This reaction was paralleled for two batches: To a mixture of tert-butyl(2-azido-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (25 g, crude)in MeOH (500 mL) was added Pd/C (1.5 g, 10% purity) and hydroxide Pd/C(1.5 g, 20% purity) under nitrogen. The resulting mixture was degassedand purged with hydrogen 3 times, and then the mixture was stirred at25° C. for 16 h under hydrogen atmosphere (15 psi). The two batches werecombined, and the mixture was filtered through a pad of celite, washedwith EtOAc, and the filtrate was concentrated under vacuum to give aresidue. The residue was purified by flash silica gel chromatography togive tert-butylN-[2-amino-5-(trifluoromethyl)-3-pyridyl]-N-methyl-carbamate (22.6 g,77.59 mmol, 49.23% yield). LCMS (ESI): m/z 292.1 [M+1]⁺.

Tert-Butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

This reaction was paralleled for two batches: To a mixture ofthiophosgene (3.55 g, 30.90 mmol, 2.37 mL) in DCM (30 mL) was added asolution of tert-butyl (2-amino-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (3 g, 10.30 mmol) in DCM (50 mL) at 0° C. and the mixture wasstirred at 25° C. for 12 h. The two batches were combined and thenpoured into saturated sodium bicarbonate at 0° C. The aqueous layer wasextracted with DCM and the combined organic phase was concentrated undervacuum. The residue was purified by column chromatography to givetert-butyl (2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (2.88 g, 8.64 mmol, 41.94% yield).

Tert-Butyl(2-(3-(imino(4-isopropylpyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of 4-isopropylpicolinimidamide (450 mg, 2.25 mmol,hydrochloride), tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl) carbamate(751.19 mg, 2.25 mmol) in DCM (20 mL) and acetone (20 mL) was added TEA(1.14 g, 11.27 mmol, 1.57 mL) at 25° C. and the mixture was stirred at25° C. for 12 h. The mixture was concentrated under vacuum to givetert-butyl(2-(3-(imino(4-isopropylpyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.12 g, crude). LCMS (ESI): m/z 497.1 [M+1]⁺.

Tert-Butyl(2-((3-(4-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-(3-(imino(4-isopropylpyridin-2-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.12 g, crude) in EtOH (20 mL) was added iodine (114.50 mg, 0.45 mmol)and hydrogen peroxide (511.48 mg, 4.51 mmol, 0.43 mL, 30% purity) at 0°C. and the mixture was stirred at 25° C. for 45 min. The mixture wasquenched by addition of saturated sodium sulfite at 0° C. andconcentrated. The aqueous phase was extracted with EtOAc and thecombined organic phase was washed with brine, dried with anhydroussodium sulfate, filtered and concentrated under vacuum to givetert-butyl (2-((3-(4-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate (1.35 g,crude). LCMS (ESI): m/z 495.1 [M+1]⁺.

N²-(3-(4-Isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine

To a mixture of tert-butyl(2-((3-(4-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.35 g, crude) in EtOAc (10 mL) was added hydrogen chloride/EtOAc (20mL, 4M) and the mixture was stirred at 25° C. for 1.5 h. The reactionmixture was concentrated under vacuum to giveN²-(3-(4-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(1.18 g, crude, hydrochloride). LCMS (ESI): m/z 395.1 [M+1]⁺.

N-(2-((3-(4-Isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a mixture ofN²-(3-(4-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(1.18 g, crude, hydrochloride) in DMF (20 mL) was added TEA (1.39 g,13.69 mmol, 1.91 mL) and Ac₂O (335.49 mg, 3.29 mmol, 0.31 mL) at 25° C.and the mixture was stirred at 40° C. for 12 h. The reaction mixture wasfiltered and the filtrate was purified by prep-HPLC (formic acidcondition; column: Phenomenex luna C18 250*50 mm*10 um; mobile phase:[H₂O (0.225% FA)-ACN]; B %: 25%-55%, 20 min) to giveN-(2-((3-(4-isopropylpyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide(395.21 mg, 0.869 mmol, 29.53% yield, 96% purity). ¹H NMR (400 MHz,DMSO-d₆) 13.14-12.48 (m, 1H), 8.95-8.83 (m, 1H), 8.58 (d, J=5.0 Hz, 1H),8.39 (s, 0.5H), 8.19 (d, J=2.1 Hz, 0.5H), 8.13-8.12 (m, 1H), 7.39 (dd,J=1.6, 5.0 Hz, 1H), 3.31 (s, 1.6H), 3.10 (s, 1.4H), 3.04-2.97 (m, 1H),2.23 (s, 1.6H), 1.73 (s, 1.4H), 1.26 (d, J=7.0 Hz, 6H). LCMS (ESI): m/z437.3 [M+1]⁺.

Example 72:N-(3-((3-(1-Isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide

N²-(3-(1-Isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine

To a solution of tert-butyl(3-((3-(1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate(360 mg, 771.61 μmol) in EtOAc (5 mL) was added hydrogen chloride/EtOAc(10 mL, 4 N). The mixture was stirred at 25° C. for 1.5 h. The mixturewas concentrated to giveN²-(3-(1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine(310 mg, crude, hydrochloride). LCMS (ESI): m/z 367.1 [M+1]⁺.

N-(3-((3-(1-Isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide

To a solution ofN²-(3-(1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine(310 mg, 769.41 μmol, hydrochloride) in DMF (10 mL) was added TEA(389.29 mg, 3.85 mmol, 535.47 μL) and Ac₂O (102.11 mg, 1.00 mmol, 93.68μL). The mixture was stirred at 40° C. for 12 h. Additional Ac₂O (40 mg)was added and the mixture was stirred at 50° C. for 12 h. The mixturewas concentrated and purified by prep-HPLC (FA condition; column:Phenomenex Luna C18 200*40 mm*10 um; mobile phase: [H₂O (0.2% FA)-ACN];B %: 1%-30%, 10 min) followed by prep-HPLC (basic condition; column:Waters Xbridge Prep OBD C18 150*40 mm*10 um; mobile phase: [H₂O (0.04%NH3H2O+10 mM NH4HCO3)-ACN]; B %: 35%-60%, 8 min) to giveN-[3-[[3-(1-isopropylpyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl]amino]pyrazin-2-yl]-N-methyl-acetamide(16.32 mg, 39.37 μmol, 5.12% yield, 99% purity). ¹H NMR (400 MHz,DMSO-d₆) 13.02-12.19 (m, 1H), 9.00 (s, 1H), 8.58-8.46 (m, 2H), 8.29-8.18(m, 1H), 7.83 (s, 1H), 6.67 (d, J=2.9 Hz, 1H), 5.06-4.92 (m, 1H), 3.35(s, 1.6H), 3.12 (s, 1.3H), 2.27 (s, 1.5H), 1.76 (s, 1.3H), 1.53 (d,J=6.6 Hz, 6H). LCMS (ESI): m/z 409.2 [M+1]⁺.

Example 73:N²-(3-(1-Isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine

Tert-Butyl(3-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate

To a mixture of tert-butyl(3-isothiocyanatopyrazin-2-yl)(methyl)carbamate (300 mg, 1.13 mmol) inDCM (20 mL) and acetone (20 mL) was added1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide(230.10 mg, 1.13 mmol) and TEA (569.94 mg, 5.63 mmol, 783.96 μL). Thereaction mixture was stirred at 20° C. for 12 h and concentrated to givetert-butyl (3-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate (600 mg,crude). LCMS (ESI): m/z 471.3 [M+1]⁺.

Tert-Butyl(3-((3-(1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate

To a mixture of tert-butyl(3-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate(600 mg, 1.27 mmol) in EtOH (10 mL) was added iodine (64.72 mg, 255.00μmol) and hydrogen peroxide (289.12 mg, 2.55 mmol, 245.02 μL, 30%purity). The reaction mixture was stirred at 25° C. for 1 h andconcentrated to give tert-butyl(3-((3-(1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate (500 mg, crude). LCMS (ESI): m/z 467.3 [M+1]⁺.

N²-(3-(1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine

To a solution of tert-butyl(3-((3-(1-isopropyl-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate(100 mg, 214.34 μmol) in EtOAc (2 mL) was added hydrogen chloride/EtOAc(4 mL, 4 N). The mixture was stirred at 25° C. for 1.5 h, concentratedand purified by prep-HPLC (HCl condition; column: Phenomenex Luna C18150*30 mm*5 um; mobile phase: [H₂O (0.04% HCl)-ACN]; B %: 25%-50%, 10min) to give N²-[3-(1-isopropylpyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl]-N³-methyl-pyrazine-2,3-diamine(35.2 mg, 85.06 μmol, 39.69% yield, 97% purity, hydrochloride). ¹H NMR(400 MHz, DMSO-d₆) 12.41 (br s, 1H), 9.38 (s, 1H), 8.74 (s, 1H), 8.60(d, J=3.1 Hz, 1H), 7.80 (d, J=3.1 Hz, 1H), 7.67 (d, J=3.1 Hz, 1H), 7.21(d, J=2.9 Hz, 1H), 5.29-5.23 (m, 1H), 2.97 (s, 3H), 1.56 (d, J=6.7 Hz,6H). LCMS (ESI): m/z 367.2 [M+1]⁺.

Example 74:N-(2-((3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

Tert-Butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate

This reaction was paralleled for two batches. To a solution of1H-pyrrolo[3,2-c]pyridine (15 g, 126.97 mmol) in DCM (150 mL) were addedTEA (21.84 g, 215.85 mmol, 30.04 mL) and N,N-dimethylpyridin-4-amine(775.60 mg, 6.35 mmol). To the mixture was added di-tert-butyldicarbonate (29.10 g, 133.32 mmol, 30.63 mL) at 0° C. and the mixturewas stirred at 25° C. for 2 h. The two batches were combined, saturatedNH₄Cl aqueous was added, and the mixture was extracted with DCM. Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and filtered. The filtrate was concentrated under reducedpressure and purified by flash silica gel chromatography to givetert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (57 g, crude). ¹H NMR(400 MHz, CDCl₃) 8.90 (s, 1H), 8.48 (d, J=5.8 Hz, 1H), 7.99 (d, J=5.3Hz, 1H), 7.62 (d, J=3.6 Hz, 1H), 6.66 (d, J=3.6 Hz, 1H), 1.70 (s, 9H).

Tert-Butyl 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

A mixture of tert-butyl 1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10 g,45.82 mmol) in MeOH (400 mL) was degassed and purged with nitrogen 3times, then Pd/C (3 g, 10% purity) and hydroxide Pd/C (3 g, 20% purity)were added. The mixture was stirred at 50° C. for 10 h under hydrogenatmosphere (50 psi). The mixture was filtered and the filtrate wasconcentrated and purified by flash silica gel chromatography to givetert-butyl 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (18.3 g,crude). ¹H NMR (4000 MHz, CDCl₃) 8.34 (d, J=5.5 Hz, 1H), 8.31 (s, 1H),7.81-7.34 (m, 1H), 4.01 (t, J=8.8 Hz, 2H), 3.14 (t, J=8.8 Hz, 2H), 1.58(s, 9H).

1-(tert-Butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 5-oxide

To a solution of tert-butyl2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (16 g, 72.64 mmol)in DCM (160 mL) was added m-CPBA (23.50 g, 108.96 mmol, 80% purity) at0° C. The mixture was stirred at 20° C. for 12 h. The mixture wasconcentrated DCM and purified by column chromatography to give1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 5-oxide(11.4 g, 48.25 mmol, 66.43% yield). LCMS (ESI): m/z 237.1 [M+1]⁺.

Tert-Butyl 6-cyano-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate

To a solution of1-(tert-butoxycarbonyl)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 5-oxide(12.9 g, 54.60 mmol) in DCM (130 mL) was added dimethylcarbamic chloride(17.61 g, 163.80 mmol, 15.06 mL) dropwise at 0° C.Trimethylsilanecarbonitrile (16.25 g, 163.80 mmol, 20.49 mL) was thenadded dropwise at 0° C. and the mixture was stirred at 25° C. for 12 h.To the mixture was added saturated sodium carbonate and it was extractedwith DCM. The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated andpurified to by flash silica gel chromatography to give tert-butyl6-cyano-2,3-dihydro-1H-pyrrolo [3,2-c]pyridine-1-carboxylate (5.59 g,22.79 mmol, 41.74% yield).

2,3-Dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile

To a solution of tert-butyl6-cyano-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (5.6 g,22.83 mmol) in DCM (45 mL) was added 2,2,2-trifluoroacetic acid (45 mL)at 0° C. The mixture was stirred at 0° C. for 3 h. The mixture wasconcentrated DCM and poured into cold saturated sodium bicarbonate. Themixture was extracted with DCM and the combined organic layers werewashed with brine, dried over anhydrous sodium sulfate and filtered. Thefiltrate was concentrated under reduced pressure to give2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile (4.6 g, crude).LCMS (ESI): m/z 146.3 [M+1]⁺.

1-Isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile

To a solution of NaH (1.90 g, 47.53 mmol, 60% purity) in DMF (50 mL) wasadded 2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile (4.6 g, 31.69mmol) at 0° C. and the mixture was stirred at 20° C. for 0.5 h. Then2-iodopropane (8.08 g, 47.53 mmol, 4.75 mL) was added at 0° C. and themixture was stirred at 20° C. for 2 h. The mixture was poured into coldsaturated NH₄Cl and extracted with EtOAc. The combined organic layerswere washed with brine, dried over anhydrous sodium sulfate andfiltered. The filtrate was concentrated and purified by flash silica gelchromatography to give crude1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile whichwas re-purified by prep-TLC to give1-isopropyl-2,3-dihydropyrrolo[3,2-c]pyridine-6-carbonitrile (255 mg,1.36 mmol, 4.30% yield) crude1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile andfurther re-purified by prep-HPLC (neutral condition; column: AgelaDuraShell C18 250*50 mm*10 um; mobile phase: [H₂O (10 mM NH₄HCO₃)-ACN];B %: 28%-28%, 22 min) to give1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile (1.05g, 5.61 mmol, 52.50% yield). LCMS (ESI): m/z 188.3 [M+1]⁺.

(Z)—N′-Hydroxy-1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide

To a solution of1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carbonitrile (200mg, 1.07 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride(85.36 mg, 1.23 mmol) and N-ethyl-N-isopropylpropan-2-amine (158.75 mg,1.23 mmol, 213.95 μL) at 25° C. The mixture was stirred at 55° C. for 2h. The mixture was concentrated to give(Z)—N′-hydroxy-1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide(565 mg, crude). LCMS (ESI): m/z 221.1 [M+1]⁺.

(Z)—N′Acetoxy-1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide

To a solution of(Z)—N′-hydroxy-1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide(565 mg, 2.57 mmol) in acetic acid (6 mL) was added Ac₂O (314.23 mg,3.08 mmol, 288.29 μL). The mixture was stirred at 25° C. for 40 min. Themixture was concentrated, poured into cold saturated sodium bicarbonate,and extracted with EtOAc. The combined organic layers were washed withbrine, dried over anhydrous sodium sulfate and filtered. The filtratewas concentrated to give(Z)—N′-acetoxy-1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide(670 mg, crude). LCMS (ESI): m/z 263.3 [M+1]⁺.

1-Isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide

To the mixture of(Z)—N′-acetoxy-1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide(670 mg, 2.55 mmol) in EtOH (30 mL) was added Pd/C (350 mg, 10% purity).The mixture was degassed and purged with hydrogen 3 times, then stirredat 40° C. for 40 min under hydrogen atmosphere (15 psi). The mixture wasfiltered and the filtrate was concentrated to give the crude product.The residue was triturated in EtOAc at 25° C. for 10 min, then the solidwas filtered and the filter cake was dried to give1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide (520mg, crude). LCMS (ESI): m/z 205.3 [M+1]⁺. ¹H NMR (400 MHz, DMSO-d₆)8.04-7.99 (m, 1H), 7.19 (s, 1H), 3.95-3.88 (m, 1H), 3.58 (t, J=8.9 Hz,2H), 3.03 (t, J=8.7 Hz, 2H), 1.17 (d, J=6.8 Hz, 6H).

Tert-Butyl(2-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

This reaction was paralleled for nine batches: To a solution of1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine-6-carboximidamide (50mg, 244.77 μmol) and tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(81.59 mg, 244.77 μmol) in DCM (4 mL) and acetone (4 mL) was added TEA(123.84 mg, 1.22 mmol, 170.35 μL). The mixture was stirred at 25° C. for12 h. 9 batches of parallel reactions were combined and concentrated togive tert-butyl (2-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.18 g, crude). LCMS (ESI): m/z 538.1 [M+1]⁺.

Tert-Butyl(2-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

This reaction was paralleled for nine batches: To a solution oftert-butyl(2-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(131 mg, 243.68 μmol) in EtOH (3 mL) was added iodine (12.37 mg, 48.74μmol) and hydrogen peroxide (55.26 mg, 487.35 μmol, 46.83 μL, 30%purity) at 0° C. The mixture was stirred at 25° C. for 7 min. All 9batches of parallel reactions were combined and quenched by addition ofsaturated sodium sulfite at 0° C. The mixture was concentrated and theaqueous phase was extracted with EtOAc. The combined organic phase waswashed with brine, dried with anhydrous sodium sulfate, filtered andconcentrated under vacuum to give tert-butyl(2-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.17 g, crude). LCMS (ESI): m/z 536.1 [M+1]⁺.

N²-(3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine

To a solution of tert-butyl(2-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.17 g, 2.18 mmol) in EtOAc (10 mL) was added hydrogen chloride/EtOAc(20 mL, 4 N) at 0° C. The mixture was stirred at 25° C. for 2 h. Themixture was concentrated to giveN²-(3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(1.03 g, crude, hydrochloride). LCMS (ESI): m/z 436.1 [M+1]⁺.

N-(2-((3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a solution ofN²-(3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(1.03 g, 2.18 mmol, hydrochloride) in DMF (15 mL) was added TEA (1.10 g,10.91 mmol, 1.52 mL) and Ac₂O (222.81 mg, 2.18 mmol, 204.41 μL). Themixture was stirred at 40° C. for 12 h. Additional Ac₂O (67 mg) wasadded, then the mixture was stirred at 40° C. for 6 h.

To the mixture was added Ac₂O (45 mg), and the mixture was stirred at40° C. for 6 h. The mixture was concentrated and purified by prep-HPLC(FA condition; column: Phenomenex luna C18 250*50 mm*10 um; mobilephase: [H₂O (0.225% FA)-ACN]; B %: 15%-45%, 20 min) followed byprep-HPLC (HCl condition; column: Phenomenex Luna C18 150*30 mm*5 um;mobile phase: [H₂O (0.04% HCl)-ACN]; B %: 20%-50%, 10 min) to giveN-(2-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide(105.22 mg, 203.19 μmol, 9.31% yield, 98% purity, hydrochloride). ¹H NMR(400 MHz, DMSO-d₆) 13.37 (s, 1H), 13.14 (s, 0.4H), 12.67 (s, 0.5H),9.02-8.88 (m, 1H), 8.48 (s, 0.5H), 8.28 (d, J=2.1 Hz, 0.5H), 7.92 (s,1H), 7.32-7.29 (m, 1H), 4.21-4.12 (m, 1H), 3.92 (t, J=8.9 Hz, 2H),3.32-3.32 (m, 1.7H), 3.17 (t, J=8.9 Hz, 2H), 3.11 (s, 1.3H), 2.24 (s,1.6H), 1.74 (s, 1.4H), 1.30-1.21 (m, 6H). LCMS (ESI): m/z 478.2 [M+1]⁺.

Example 75:N-(3-((3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide

Tert-Butyl(3-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate

To a mixture of tert-butyl(3-isothiocyanatopyrazin-2-yl)(methyl)carbamate (300 mg, 1.13 mmol) inDCM (20 mL) and acetone (20 mL) was added1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboximidamide(230.10 mg, 1.13 mmol) and TEA (569.94 mg, 5.63 mmol, 0.78 mL), then thereaction mixture was stirred at 25° C. for 12 h. The reaction mixturewas concentrated to givetert-butyl(3-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate(540 mg, crude). LCMS (ESI): m/z 471.2 [M+1]⁺.

Tert-Butyl(3-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate

To a mixture of tert-butyl(3-(3-(imino(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridine-5-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate(540 mg, crude) in EtOH (10 mL) was added iodine (58.25 mg, 0.23 mmol)and hydrogen peroxide (260.21 mg, 2.29 mmol, 0.22 mL, 30% purity) at 0°C. and the reaction mixture was stirred at 25° C. for 10 min. Thereaction mixture was quenched with sodium sulfite aqueous andconcentrated. The residue was dissolved in EtOAc and washed with H₂O.The organic layer was dried over anhydrous sodium sulfate, concentrated,and triturated with MTBE/EtOAc (5:1) at 25° C. for 10 min. The mixturewas filtered and the filter cake was dried to give tert-butyl(3-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate(320 mg, 682.92 μmol, 59.51% yield). LCMS (ESI): m/z 469.1 [M+1]⁺. ¹HNMR (400 MHz, DMSO-d₆) 12.58 (s, 1H), 8.45-8.40 (m, 1H), 8.18 (s, 1H),7.90 (s, 1H), 7.82 (s, 1H), 3.99-3.96 (m, 1H), 3.45 (t, J=8.7 Hz, 2H),3.16 (s, 3H), 3.05-3.00 (m, 2H), 1.39-1.24 (m, 9H), 1.15 (d, J=6.6 Hz,6H).

N²-(3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine

The mixture of tert-butyl(3-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate(320 mg, 682.92 μmol) in EtOAc (5 mL) was added hydrogen chloride/EtOAc(5 mL, 4 M) and stirred at 25° C. for 5 h. The reaction mixture wasconcentrated to giveN²-(3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine(276 mg, crude, hydrochloride). LCMS (ESI): m/z 369.1 [M+1]⁺.

N-(3-((3-(1-Isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide

To a mixture ofN²-(3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)-N-methylpyrazine-2,3-diamine(225 mg, 0.61 mmol) in DMF (8 mL) was added Ac₂O (81.04 mg, 0.80 mmol)and TEA (308.96 mg, 3.05 mmol, 0.42 mL) and the mixture was stirred at50° C. for 32 h. The reaction mixture was filtered and the filtrate waspurified by prep-HPLC (base condition, column: Welch Xtimate C18 250*50mm*10 um; mobile phase: [H₂O (0.04% NH₃H₂O+10 mM NH₄HCO₃)-ACN]; B %:25%-45%, 10 min) to giveN-(3-((3-(1-isopropyl-2,3-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide(20.32 mg, 0.045 mmol, 7.57% yield, 91% purity). ¹H NMR (400 MHz,DMSO-d₆) 13.03-12.18 (m, 1H), 8.59-8.41 (m, 1H), 8.27-8.17 (m, 1H), 7.91(s, 1H), 7.82 (s, 1H), 4.01-3.92 (m, 1H), 3.45 (t, J=8.7 Hz, 2H), 3.32(s, 1.7H), 3.09 (s, 1.3H), 3.01 (t, J=8.5 Hz, 2H), 2.25 (s, 1.4H), 1.74(s, 1.3H), 1.15 (d, J=6.5 Hz, 6H). LCMS (ESI): m/z 411.3 [M+1]⁺.

Example76:1-(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one

4-Chloro-N-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)butanamide

To a mixture of 2-chloro-5-(trifluoromethyl)pyridin-3-amine (9.98 g,50.77 mmol) in DCM (150 mL) was added TEA (10.28 g, 101.55 mmol, 14.13mL) and 4-chlorobutanoyl chloride (12.89 g, 91.39 mmol, 10.23 mL) at 0°C. The mixture was stirred at 40° C. for 12 h. To the reaction was addedTEA (2.57 g, 25.39 mmol, 3.53 mL) and 4-chlorobutanoyl chloride (3.58 g,25.39 mmol, 2.84 mL) at 25° C. The mixture was stirred at 40° C. for 16h. The reaction mixture was concentrated and purified by flash silicagel chromatography to give4-chloro-N-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)butanamide (23 g,crude). LCMS (ESI): m/z 300.9 [M+1]⁺.

1-(2-Chloro-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one

Two batches in parallel: To a mixture of4-chloro-N-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)butanamide (11.4 g,37.86 mmol) in ACN (250 mL) was added potassium tert-butoxide (8.50 g,75.72 mmol) at 25° C. and the reaction was stirred at 80° C. for 12 h.The combined reaction mixture was concentrated under reduced pressureand purified by flash silica gel chromatography to give1-(2-chloro-5-(trifluoromethyl) pyridin-3-yl)pyrrolidin-2-one (5.6 g,21.16 mmol, 27.95% yield). LCMS (ESI): m/z 264.9 [M+1]⁺.

1-(2-Amino-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one

A mixture of1-(2-chloro-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one (2.6 g,9.82 mmol) in ammonium hydroxide (30 mL, 25% purity) and THE (10 mL) wasstirred at 100° C. for 16 h. The reaction mixture was concentrated andpurified by flash silica gel chromatography to give1-(2-amino-5-(trifluoromethyl)pyridin-3-yl) pyrrolidin-2-one (1.77 g,7.22 mmol, 73.47% yield). LCMS (ESI): m/z 246.1 [M+1]⁺. ¹H NMR (400MHz-DMSO-d₆) δ 8.23 (d, J=1.1 Hz, 1H), 7.67 (d, J=2.1 Hz, 1H), 6.78 (brs, 2H), 3.58 (t, J=6.9 Hz, 2H), 2.38 (t, J=8.0 Hz, 2H), 2.17-2.09 (m,2H).

1-(2-Isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one

To a solution of thiophosgene (1.13 g, 9.79 mmol, 750.29 μL) in DCM (10mL) was added a solution of1-(2-amino-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one (0.8 g, 3.26mmol) in DCM (10 mL) at 0° C. The mixture was stirred at 25° C. for 12h. The mixture was poured into saturated sodium bicarbonate at 0° C. andextracted with DCM. The combined organic phase was concentrated undervacuum and purified by column chromatography to give1-(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl) pyrrolidin-2-one(390 mg, 1.36 mmol, 41.61% yield). LCMS (ESI): m/z 288.0 [M+1]⁺.

5-Isopropoxy-N-((3-(2-oxopyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide

To a mixture of1-(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one(195 mg, 678.83 μmol), 5-isopropoxypicolinimidamide (121.66 mg, 678.83μmol) in DCM (10 mL) and acetone (10 mL) was added TEA (343.45 mg, 3.39mmol, 472.42 μL) at 25° C. and the mixture was stirred at 25° C. for 12h. The mixture was concentrated under vacuum to give5-isopropoxy-N-((3-(2-oxopyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide(316 mg, crude). LCMS (ESI): m/z 467.1 [M+1]⁺.

1-(2-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one

To a mixture of5-isopropoxy-N-((3-(2-oxopyrrolidin-1-yl)-5-(trifluoromethyl)pyridin-2-yl)carbamothioyl)picolinimidamide(0.567 g, 1.22 mmol) in EtOH (8 mL) was added iodine (61.70 mg, 243.10μmol) and hydrogen peroxide (275.63 mg, 2.43 mmol, 233.58 μL, 30%purity) at 0° C. and the mixture was stirred at 25° C. for 15 min. Themixture was quenched by addition of saturated sodium sulfite at 0° C.and concentrated. The aqueous phase was extracted with EtOAc and thecombined organic phase was washed with brine, dried with anhydroussodium sulfate, filtered and concentrated under vacuum. The residue waspurified by prep-HPLC (FA condition; column: Phenomenex Luna C18 200*40mm*10 um; mobile phase: [H₂O (0.2% FA)-ACN]; B %: 50%-80%, 10 min) togive1-(2-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)pyrrolidin-2-one(293.45 mg, 571.81 μmol, 47.04% yield, 99% purity). ¹H NMR (400 MHz,DMSO-d₆) 12.52 (s, 1H), 8.86 (d, J=1.0 Hz, 1H), 8.33 (d, J=2.8 Hz, 1H),8.28 (d, J=1.9 Hz, 1H), 8.18 (d, J=8.6 Hz, 1H), 7.52 (dd, J=2.9, 8.9 Hz,1H), 4.83-4.74 (m, 1H), 3.79 (t, J=6.9 Hz, 2H), 2.49-2.43 (m, 2H), 2.22(q, J=7.5 Hz, 2H), 1.32 (d, J=6.0 Hz, 6H). LCMS (ESI): m/z 465.1 [M+1]⁺.

Example 77:N-(2-((3-(2-Isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

2-Chloro-4,5-bis(chloromethyl)pyridine

To a mixture of (6-chloropyridine-3,4-diyl)dimethanol (3.7 g, 21.31mmol) in DCM (40 mL) was added sulfurous dichloride (12.68 g, 106.57mmol, 7.73 mL). The reaction mixture was stirred at 50° C. for 2 h undernitrogen and then concentrated to give2-chloro-4,5-bis(chloromethyl)pyridine (4.5 g, crude).

6-Chloro-2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine

To a mixture of 2-chloro-4,5-bis(chloromethyl)pyridine (4.5 g, crude) inDCM (50 mL) was added propan-2-amine (6.32 g, 106.89 mmol, 9.18 mL) at20° C. and the reaction mixture was stirred at 50° C. for 12 h undernitrogen. The crude product was purified by column chromatography onsilica gel to give 6-chloro-2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (1.8 g, 9.15 mmol, 42.81% yield). LCMS (ESI): m/z 197.3 [M+1]⁺.

Methyl 2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate

To a mixture of6-chloro-2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine (1.8 g, 9.15mmol) in MeOH (40 mL) was added TEA (1.85 g, 18.30 mmol, 2.55 mL) and[1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (669.67 mg,0.92 mmol). The reaction mixture was stirred at 70° C. for 12 h undercarbon monoxide (50 psi). The reaction mixture was concentrated andpurified by column chromatography on silica gel to give methyl2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-6-carboxylate (1.8 g,8.17 mmol, 89.29% yield). LCMS (ESI): m/z 221.3 [M+1]⁺.

2-Isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide

The mixture of methyl2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxylate (2.0 g,9.08 mmol) in ammonia/methanol (7 M, 20 mL) was stirred at 100° C. for12 h in a sealed tube. The reaction mixture was concentrated to give2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-6-carboxamide (1.8 g,crude).

2-Isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonitrile

A mixture of2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboxamide (1.7 g,8.28 mmol) in phosphoryl trichloride (40 mL) was stirred at 90° C. for 2h. The reaction mixture was concentrated under vacuum and dissolved inEtOAc. The mixture was poured into ice H₂O slowly and solid sodiumbicarbonate was added until pH 8 was reached. Organic phases wereextracted with EtOAc and the combined organic layers were concentratedand purified by column chromatography to give2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonitrile (1.25g, 6.68 mmol, 80.60% yield). LCMS (ESI): m/z 188.2 [M+1]⁺. ¹H NMR (400MHz, DMSO-d₆) 8.64 (s, 1H), 7.96 (s, 1H), 3.95 (d, 4H), 2.80-2.73 (m,1H), 1.09 (d, J=6.4 Hz, 6H).

2-Isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboximidamide

To a mixture of2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carbonitrile (1.25g, 6.68 mmol) in MeOH (20 mL) was added a solution of sodium (76.74 mg,3.34 mmol) in MeOH (1 mL) at 25° C. and the mixture was stirred at 25°C. for 12 h. To the reaction mixture was added NH₄Cl (535.65 mg, 10.01mmol) at 25° C. and stirred at 70° C. for 2 h. The reaction mixture wasconcentrated and triturated with MTBE:EtOAc (10:1, 22 mL) for 10 min.The solution was filtered and the filter cake was collected andconcentrated under reduced pressure to give2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c] pyridine-6-carboximidamide(1.49 g, 6.19 mmol, 92.71% yield, hydrochloride). LCMS (ESI): m/z 205.2[M+1]⁺.

Tert-Butyl(2-(3-(imino(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-6-carboximidamide (0.5g, 2.08 mmol, hydrochloride), tert-butyl(2-isothiocyanato-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(692.32 mg, 2.08 mmol) in DCM (10 mL) and acetone (10 mL) was added TEA(1.05 g, 10.38 mmol, 1.45 mL) at 25° C. The mixture was stirred at 25°C. for 12 h and then concentrated under vacuum to give tert-butyl(2-(3-(imino(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.12 g, crude). LCMS (ESI): m/z 538.2 [M+1]⁺.

Tert-Butyl(2-((3-(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate

To a mixture of tert-butyl(2-(3-(imino(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)methyl)thioureido)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(1.12 g, crude) in EtOH (16 mL) was added iodine (105.75 mg, 0.42 mmol)and hydrogen peroxide (472.43 mg, 4.17 mmol, 0.4 mL, 30% purity) at 0°C. The mixture was stirred at 25° C. for 15 min and then quenched byaddition of saturated sodium sulfite at 0° C. The solution wasconcentrated under vacuum and triturated with MTBE:EtOAc (3:1, 20 mL)for 10 min. The suspension was filtered, the filter cake dried undervacuum and was suspended in DCM. The suspension was filtered, thefiltrate was concentrated under vacuum to give tert-butyl(2-((3-(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(810 mg, 1.51 mmol, 72.59% yield). LCMS (ESI): m/z 536.1 [M+1]⁺.

N²-(3-(2-Isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine

A mixture of tert-butyl(2-((3-(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)(methyl)carbamate(785 mg, 1.47 mmol) in EtOAc (10 mL) and hydrogen chloride/EtOAc (20 mL,4 M) was stirred at 25° C. for 2 h. The reaction mixture wasconcentrated under vacuum to giveN²-(3-(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(691 mg, crude, hydrochloride). LCMS (ESI): m/z 436.1 [M+1]⁺.

N-(2-((3-(2-Isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide

To a mixture ofN²-(3-(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)-N³-methyl-5-(trifluoromethyl)pyridine-2,3-diamine(691 mg, crude, hydrochloride) and Ac₂O (239.16 mg, 2.34 mmol, 0.22 mL)in DMF (15 mL) was added TEA (740.81 mg, 7.32 mmol, 1.02 mL) at 25° C.and then the mixture was stirred at 45° C. for 12 h. Additional Ac₂O(44.84 mg, 0.44 mmol) was added at 25° C. and then stirred at 45° C. for5 h. The reaction mixture was concentrated under vacuum and purified byprep-HPLC (formic acid condition; column: Phenomenex luna C18 250*80mm*10 um; mobile phase: [H₂O (0.225% FA)-ACN]; B %: 10%-40%, 20 min) togive a crude product. Then the crude product was re-purified byprep-HPLC (formic acid condition; column: Phenomenex Luna C18 200*40mm*10 um; mobile phase: [H₂O (0.2% FA)-ACN]; B %: 10%-50%, 10 min) togive a crude product. The crude product was re-purified by prep-HPLC(neutral condition; column: Waters Xbridge BEH C18 100*25 mm*5 um;mobile phase: [H₂O (10 mM NH4HCO3)-ACN]; B %: 55%-85%, 8 min) to give acrude product. Then the crude product was re-purified by prep-HPLC(hydrogen chloride condition; column: Phenomenex Luna C18 150*30 mm*5um; mobile phase: [H₂O (0.04% HCl)-ACN]; B %: 20%-50%, 10 min) to giveN-(2-((3-(2-isopropyl-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-yl)-1,2,4-thiadiazol-5-yl)amino)-5-(trifluoromethyl)pyridin-3-yl)-N-methylacetamide (32.9 mg, 62.73 μmol, 4.30% yield, 98%purity, hydrochloride). ¹H NMR (400 MHz, DMSO-d₆) 13.28-12.60 (m, 1H),12.19 (br s, 1H), 8.96-8.84 (m, 1H), 8.73 (s, 1H), 8.45-8.18 (m, 2H),4.93-4.82 (m, 2H), 4.73-4.65 (m, 2H), 3.73-3.68 (m, 1H), 3.30 (s, 1.5H),3.10 (s, 1.5H), 2.22 (s, 1.5H), 1.73 (s, 1.3H), 1.38 (d, J=6.4 Hz, 6H).LCMS (ESI): m/z 478.2 [M+1]⁺.

Example 78:N-(3-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide

Tert-Butyl N-tert-butoxycarbonyl-N-(3-chloropyrazin-2-yl)carbamate

To a mixture of 3-chloropyrazin-2-amine (20 g, 154.38 mmol) anddi-tert-butyl dicarbonate (67.39 g, 308.77 mmol, 70.94 mL) in DCM (400mL) was added N,N-dimethylpyridin-4-amine (1.89 g, 15.44 mmol) and thenthe reaction mixture was stirred at 40° C. for 2 h. The reaction mixturewas washed with H₂O and extracted with DCM. The combined organic layerswere dried over anhydrous sodium sulfate and concentrated to givetert-butyl N-tert-butoxycarbonyl-N-(3-chloropyrazin-2-yl)carbamate (50g, crude).

Tert-Butyl (3-chloropyrazin-2-yl)carbamate

To the mixture of tert-butylN-tert-butoxycarbonyl-N-(3-chloropyrazin-2-yl)carbamate (50 g, crude) inMeOH (400 mL) was added a solution of sodium hydroxide (11.43 g, 285.74mmol) in H₂O (100 mL) and the reaction mixture was stirred at 20° C. for1 h. The reaction mixture was concentrated, and the H₂O layer wasextracted with EtOAc. The combined organic layers were dried overanhydrous sodium sulfate and concentrated to give tert-butyl(3-chloropyrazin-2-yl)carbamate (30 g, crude).

Tert-Butyl (3-chloropyrazin-2-yl)(methyl)carbamate

To a solution of tert-butyl (3-chloropyrazin-2-yl)carbamate (20 g,crude) in DMF (200 mL) was added sodium hydride (3.83 g, 95.79 mmol, 60%purity) in portions at 0° C. After addition, the reaction mixture wasstirred at 0° C. for 0.5 h, then iodomethane (12.98 g, 91.44 mmol, 5.69mL) was added at 0° C. The reaction mixture was stirred at 20° C. for 1h. The reaction mixture was poured into saturated ammonium chlorideaqueous and then extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to give tert-butyl(3-chloropyrazin-2-yl)(methyl)carbamate (21.22 g, crude). LCMS (ESI):m/z 244.1 [M+1]⁺.

Tert-Butyl (3-azidopyrazin-2-yl)(methyl)carbamate

To a mixture of sodium azide (8.00 g, 123.11 mmol) in DMSO (150 mL) wasadded tert-butyl (3-chloropyrazin-2-yl)(methyl)carbamate (10 g, crude)and the reaction mixture was stirred at 100° C. for 16 h. To thereaction mixture was added to H₂O and the mixture was extracted withEtOAc, the combined organic layers were dried over anhydrous sodiumsulfate and concentrated to give tert-butyl(3-azidopyrazin-2-yl)(methyl) carbamate (9.5 g, crude). LCMS (ESI): m/z251.3 [M+1]⁺.

Tert-Butyl (3-aminopyrazin-2-yl)(methyl)carbamate

To a mixture of tert-butyl (3-azidopyrazin-2-yl)(methyl)carbamate (9.5g, crude) in MeOH (150 mL) was added Pd/C (1.2 g, 10% purity) andpalladium hydroxide/carbon (1.2 g, 8.54 mmol, 20% purity). The reactionmixture was stirred at 20° C. for 12 h under hydrogen atmosphere (15psi). The reaction mixture was filtered and the filtrate wasconcentrated and purified by column chromatography to give tert-butyl(3-aminopyrazin-2-yl)(methyl) carbamate (4.3 g, 19.17 mmol, 50.51%yield).

Tert-Butyl (3-isothiocyanatopyrazin-2-yl)(methyl)carbamate

A solution of thiocarbonyl dichloride (3.08 g, 26.75 mmol, 2.05 mL) inDCM (50 mL) was cooled to 0° C., then a solution of tert-butyl(3-aminopyrazin-2-yl)(methyl) carbamate (2 g, 8.92 mmol) in DCM (30 mL)was added dropwise to the above mixture at 0° C. After addition, thereaction mixture was stirred at 0° C. for 2 h. The reaction mixture wasconcentrated and purified by flash column chromatography to givetert-butyl (3-isothiocyanatopyrazin-2-yl) (methyl)carbamate (900 mg,3.38 mmol, 37.89% yield). LCMS (ESI): m/z 267.3 [M+1]⁺.

Tert-Butyl(3-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate

To a mixture of tert-butyl(3-isothiocyanatopyrazin-2-yl)(methyl)carbamate (200 mg, 0.75 mmol) and5-isopropoxypicolinimidamide (134.59 mg, 0.75 mmol) in DCM (20 mL) andacetone (20 mL) was added TEA (379.96 mg, 3.75 mmol, 0.52 mL) then thereaction mixture was stirred at 20° C. for 3 h. The reaction mixture wasconcentrated to give tert-butyl(3-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate (340 mg, crude). LCMS (ESI): m/z 446.3 [M+1]⁺.

Tert-Butyl(3-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate

To a mixture of tert-butyl(3-(3-(imino(5-isopropoxypyridin-2-yl)methyl)thioureido)pyrazin-2-yl)(methyl)carbamate (340 mg, crude) in EtOH (10 mL) was addediodine (38.74 mg, 0.15 mmol) and hydrogen peroxide (173.05 mg, 1.53mmol, 0.15 mL, 30% purity). The reaction mixture was stirred at 20° C.for 0.2 h. The reaction mixture was quenched by saturated sodium sulfiteaqueous and concentrated. The residue was extracted with EtOAc and theorganic layer was dried over anhydrous sodium sulfate and concentratedto give tert-butyl(3-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate (300 mg, crude). LCMS (ESI): m/z 444.1 [M+1]⁺.

N²-(3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine

The mixture of tert-butyl(3-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)(methyl)carbamate (300 mg, crude) in hydrogenchloride/EtOAc (4 M, 5 mL) and EtOAc (5 mL) was stirred at 20° C. for 1h. The reaction mixture was concentrated to giveN²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine(260 mg, crude, hydrochloride salt). LCMS (ESI): m/z 344.2 [M+1]⁺.

N-(3-((3-(5-Isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide

To a mixture ofN²-(3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)-N³-methylpyrazine-2,3-diamine(260 mg, crude, hydrochloride) in DMF (5 mL) was added TEA (346.30 mg,3.42 mmol, 0.47 mL) and Ac₂O (90.84 mg, 0.89 mmol) and the reactionmixture was stirred at 45° C. for 12 h. The crude product was purifiedby prep-HPLC (formic acid condition, Phenomenex Luna C18 100*30 mm*5 um;mobile phase: [H₂O (0.2% FA)-ACN]; B %: 30%-45%, 12 min) to giveN-(3-((3-(5-isopropoxypyridin-2-yl)-1,2,4-thiadiazol-5-yl)amino)pyrazin-2-yl)-N-methylacetamide(92.34 mg, 0.237 mmol, 35.83% yield, 99% purity). ¹H NMR (400 MHz,DMSO-d₆) 13.13-12.08 (m, 1H), 8.60-8.42 (m, 1H), 8.33 (s, 1H), 8.26-8.14(m, 2H), 7.52 (d, J=7.0 Hz, 1H), 4.81-4.76 (m, 1H), 3.30 (s, 2.3H), 3.10(s, 0.7H), 2.26 (s, 1.5H), 1.74 (br s, 1.5H), 1.32 (d, J=5.8 Hz, 6H).LCMS (ESI): m/z 386.1 [M+1]⁺.

Example 79:4-Methyl-N-[5-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-3-yl]pyridin-2-amine

2-(5-Bromo-1,2,4-thiadiazol-3-yl)-3-methylpyridine

To a stirred solution of 3-bromo-5-chloro-1,2,4-thiadiazole (522 mg,2.62 mmol) in 1, 4-dioxane (25 mL) 3-methyl-2-(tributylstannyl)pyridine(1 g, 2.62 mmol) was added and the reaction mixture was degassed withargon for 10 min. Pd (PPh₃)₄ (151 mg, 0.13 mmol) was added followed bycopper(I) thiophene-2-carboxylate (5 mg, 0.26 mmol) and degassed for anadditional 5 min. The resulting mixture was stirred at 25° C. for 16 h.and diluted with EtOAC, H₂O and filtered through a short pad of celite.The filtrate was extracted with EtOAc and the combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by columnchromatography to afford 2-(4-bromo-1,3-thiazol-2-yl)-3-methylpyridine(170 mg, 25%). LCMS (ESI): m/z 257.8 [M+1]⁺.

4-Methyl-N-[5-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-3-yl]pyridin-2-amine

To a stirred solution of 2-(4-bromo-1,3-thiazol-2-yl)-3-methylpyridine(150 mg, 0.59 mmol) in 1, 4-dioxane (5 mL) 4-methylpyridin-2-amine (126mg, 1.17 mmol) and Cs₂CO₃ (384 mg, 1.17 mmol) was added and degassedwith argon for 10 min. Xantphos (51 mg, 0.09 mmol) and Pd₂(dba)₃ (27 mg,0.03 mmol) were added and the mixture was degassed for an additional 5min. The resulting mixture was heated to 110° C. for 16 h then cooled,diluted with EtOAc, H₂O and filtered through a short pad of celite. Thefiltrate was extracted with EtOAc and the combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated underreduced pressure. The crude compound was purified by prep-HPLC to afford4-methyl-N-[5-(3-methylpyridin-2-yl)-1,2,4-thiadiazol-3-yl]pyridin-2-amine(35 mg, 21%). LCMS (ESI): m/z 283.8 [M+1]⁺.

Compounds 331-351 in Table 1 can be prepared using analogous methodsdescribed herein and those known in the art.

In Vitro Parasite Motility Assays

Parasite Motility Assays.

Adult and microfilariae B. malayi and B. pahangi parasites, harvestedfrom infected jirds, were procured from the NIAID/NIH FilariasisResearch Reagent Resource Center (FR3). Adult and microfilariae of L.sigmodontis were procured from TRS labs Inc. (Athens, Ga.). Adult wormswere plated in 24-well plates with 2 mL of Advanced RPMI 1640 medium(Invitrogen) supplemented with 25 mM HEPES, 2 mM L-Glutamine(Invitrogen), 100 U/mL Penicillin (Invitrogen), 100 g/mL Streptomycin(Invitrogen), 2.5 g/mL Amphotericin B solution (Invitrogen), and 5% heatinactivated fetal bovine serum and placed in a 37° C. humidifiedincubator with 5% CO₂. After 24 h, adult worms were selected based uponmotility as described below. After scoring for motility, 4-6 highlymotile worms were selected for each treatment group and were transferredto new plates. Microfilariae were centrifuged at 5000×g for 5 min, andre-suspended in 2 ml of media. Microfilarial density was determinedusing a hemocytometer and were plated in a 96-well plate at 80microfilariae/well with 200 μL of complete media. Treatment groupsreceived compounds (0.1% DMSO) at 1 μM and 100 nM with 0.1% DMSO as avehicle control. Cultures were incubated at 37° C. in a humidifiedincubator with 5% CO₂. Worms were transferred into a new platecontaining fresh media and drug every 48 h. Parasite and microfilariaemotility were given a score from 0 to 4 with 4, rapid movement andlargely coiled; 3, moderated movement and uncoiled; 2, slow movement anduncoiled; 1, twitching movement and uncoiled; 0, no motility (dead). Themotility of the worms and microfilariae were evaluated every 24 h andanalyzed by a one sided unpaired Student's t-test using Microsoft Excel.Experiments were performed 2-3 times with similar results.

Onchocerciasis: In Vitro Screening Model Onchocerca gutturosa

Parasite and Cell Cultures. Onchocerca gutturosa Adult Male Worms wereobtained by dissection from the nuchal ligament connective tissues ofnaturally infected cattle, from Gambia, W Africa.

The worms were maintained for at least 24 h in culture before use inEagles Minimum Essential Medium with Earl's Salts (Gibco, UK)+10% heatinactivated new born calf serum (Gibco, UK)+antibiotic cover of 200units/ml penicillin, 200 μg/ml streptomycin and 0.5 μg/ml amphotericin B(Sigma, UK). Only normally active specimens were used in the test. Allcultures and assays were conducted at 37° C. under an atmosphere of 5%CO₂ in air.

Drug Sensitivity Assays.

Compound stock solutions were prepared in 100% DMSO unless otherwiseindicated and diluted into the medium. Any unused compound stocks werestored at −20° C. Assays were performed in sterile 24-well (2 ml) plates(Falcon, UK).

Worms were then transferred individually to each well of the plate usingfine forceps. Worm viability was assessed using 2 parameters:

-   -   The measurement of mean worm motility scores on a scale of 0        (immotile) to 10 (maximum) every 24 h, terminating at 120 h,        using an Olympus inverted microscope.    -   The biochemical evaluation of worm viability using MTT/formazan        colorimetry. The MTT assay was carried out after the last        motility reading (120 h). Single intact worms were placed in        each well of a 48-well plate (Falcon, UK) containing 0.5 ml of a        solution consisting of 0.5 mg/ml MTT (Sigma UK) in phosphate        buffered saline, and then incubated for 30 min at 37° C. The        worms were removed, blotted carefully, and individually        transferred to separate wells of a 96-well microtiter plate,        each containing 200 μl of DMSO to solubilize the formazan. After        1 h the plate was gently agitated to disperse the color evenly        and the absorbance value (optical density) of the resulting        formazan solution was determined at 490 nm using a multi-well        scanning spectrophotometer (Elisa-reader, Dynatech, UK).        Inhibition of formazan formation was correlated with worm damage        or death.

Primary Screen.

New compounds were usually tested at 1.25×10⁻⁵ M. Also expressed inμg/ml. Test drugs (2 worms/group) were compared to untreated controls (6worms/group) and a positive control (standard drug, 6 worms/group). Thestandard used was Immiticide (Merial): this drug produces a reduction inmotility of 100%, and mean inhibition of formazan formation of ˜85%. Theapproximate motility EC₅₀ for Immiticide was 3×10⁻⁷ M, and forivermectin was 1×10⁻⁸ M. The readouts are: Motility score (mean %reduction at 120 h) MTT colorimetry (mean inhibition of formazanformation).

A test compound was considered active if there was a 50% or greaterreduction in motility score and/or a 50% or greater inhibition offormazan formation compared to untreated controls.

Compounds were classified as moderately active if there was a 50-99%reduction in motility and/or inhibition of formazan, or highly active at100%/lower concentrations.

Secondary Screen.

All active compounds were re-tested. Serial 1 in 4 drug dilutions wascarried out to find activity endpoint and EC₅₀ values for motilityreduction and inhibition of formazan formation were produced. EC₅₀values were determined using Excel or Origin V7 scientific graphing anddata analysis software.

Heartworm Screen Dirofilaria immitis (D. immitis)

Dirofilaria immitis, Microfilaria (DiMF) Assay.

Compounds were dissolved and serially diluted in DMSO. Aliquots werespotted to the empty wells of assay plates. Media and microfilariae ofDirofilaria immitis were added to each well to dilute the test compoundsto the desired concentrations. Assay plates were incubated forapproximately 72 hours, and the larvae in each well were observedmicroscopically for drug effect. Microfilariae in each well wereassessed subjectively for survival or paralysis, and results werereported as Minimum Effective Dose (MED).

Dirofilaria immitis, L4 Stage (DiL4) Assay.

Compounds were dissolved and serially diluted in DMSO. Aliquots werespotted to the empty wells of assay plates. Media and 4th stage larvae(L4) of Dirofilaria immitis were added to each well to dilute the testcompounds to the desired concentrations. Assay plates were incubated forapproximately 72 hours, and the larvae in each well were observedmicroscopically for drug effect. Larvae in each well were assessedsubjectively for survival or paralysis, and results were reported asMinimum Effective Dose (MED).

The compounds described herein demonstrated nematocidal activity againsteither Dirofilaria immitis (Larva stage 4 (DiL4)) and/or Dirofilariaimmitis (microfilaria (DiMF)) as determined by reductions in nematodemotility either by paralysis or death. Active and selective (DiL4 vs.DiMF potency) example compounds were subsequently evaluated in heartwormpositive dog studies to correlate the in vitro selectivity profile within vivo effects on circulating microfilariae.

Activity of the Heterocyclic Compounds in the parasite motility assaysis shown in Table 1.

In Vivo Filariasis Assays

L. sigmodontis In Vivo Assays.

The infection of mice and jirds can be either initiated by the naturalroute, exposure of mites containing infective third stage larvae (L3) ofL. sigmodontis, or via the injection (subcutaneous, intraperitoneal orintravenous) of a known number of L3 larvae (G. Karadjian et al.,Migratory phase of Litomosoides sigmodontis filarial infective larvae isassociated with pathology and transient increase of S100A9 expressingneutrophils in the lung, PLoS Negl Trop Dis 11, e0005596 (2017)). Uponinfection L3 larvae migrate from the site of inoculation within 2-6 daysvia the lymphatics to the thoracic cavity, where they molt around 10days post infection (dpi) into 4th stage larvae and around 30 dpi intoadult worms. Approximately 56 dpi adult female worms start to releasemicrofilariae that enter the peripheral blood. In BALB/c mice, adultworm burden starts to decline around 70 dpi and by 100 dpi at which mostof the adult worms are cleared. Jirds harbor the adult worms for morethan one year.

L. sigmodontis Mouse Model.

The L. sigmodontis mouse model allows the analysis of the activity ofcompounds on the adult worm or the development into adult worms.

L. sigmodontis Jird Model.

In order to assess the efficacy of drug candidates during chronic,patent infection the L. sigmodontis jird model was used. In general,treatment with drug candidates was initiated 12 weeks post infection andonly microfilariae-positive jirds were included in the experiments.Necropsies were performed in general 8-16 weeks post treatment. Thisextended time between initiation of treatment and necropsy allowed toidentify the macrofilaricidal (adult worm killing) efficacy of slowacting compounds. The jird model allowed the assessment of the in vivoimpact of compounds on microfilariae over time. Compounds with strongmicrofilaricidal efficacy clear the microfilariae from peripheral bloodwithin a short period of time. Compounds with an adult worm sterilizingor macrofilaricidal efficacy (lacking a microfilaricidal efficacy) leadto a delayed reduction of the microfilaremia that exceeds 4 weeks posttreatment start. Additional analysis at the time of necropsy includedthe quantification of adult worms, ratios of female and male adultworms, and motility of adult worms at the time of necropsy. Remainingfemale adult worms were assessed for their embryogenesis and thereforesterilizing effects of compounds. Embryograms from female adult wormsincluded the quantification of early developmental stages (egg/morulae)and later stages (pretzel stage & stretched microfilariae) according to(S. Ziewer et al., Immunization with L. sigmodontis MicrofilariaeReduces Peripheral Microfilaraemia after Challenge Infection byInhibition of Filarial Embryogenesis, PLoS Negl Trop Dis 6, e1558(2012)). Lack of early and/or later developmental embryonic stagessuggested a sterilizing effect of the compounds. Additional histologicaland TEM analysis was applied to analyze any tissue damages caused by thedrug candidates that may be associated with permanent sterilization.

The L. sigmodontis jird model assessed the macrofilaricidal efficacy ofcompounds, their impact on microfilaremia, female worm embryogenesis andsterilization.

The Heterocyclic Compounds provided herein were tested and showedactivity in both L. sigmodontis mouse and L. sigmodontis jird modelassays performed as described herein, with some compounds showingmacrofilaricidal activity, some compounds showing microfilaricidalactivity, and some compounds showing macrofilaricidal selectivity.

In some embodiments, the compounds disclosed herein surprisinglypresented distinct activity between parasitic nematodes in adult andjuvenile stage. In some such embodiments, the compounds disclosed hereinwere found to be selectively effective against adult filarial nematodes(i.e., were macroselective). Therefore, the compounds disclosed hereinhave the potential to be potent anti-filarial drugs.

Heartworm Dog Studies.

Dogs with pre-existing heartworm infections, via surgicaltransplantation were used for these studies. To confirm that the dogshad circulating microfilariae, blood samples were taken from each dogand examined for microfilariae by using the modified Knott's method. Alldog cohorts included in the studies exhibited average microfilariaecounts of at least 15,000 MF/mL of the blood (pre-dose). Onapproximately Day −7, dogs were randomly allocated to treatments (threeanimals per treatment group) based on Day −7 MF counts. Dogs were fastedovernight prior to dosing and fed immediately following dosing of thetest articles. Compounds were administered by point dosing in oralliquid-filled capsules on Day 0. Blood samples were collected to measureMF counts on Days 0 (pre-dose and 2 hours post-dose), 1, 2, 7, 21 and28. Clinical observations were conducted by a suitably experiencedveterinarian on days −7, 0 (immediately prior to treatment, 1-2 hourspost-treatment), 1 and 2 whereby any abnormal clinical signs weredocumented using standard veterinary medical terminology. Additionally,general health observations were conducted throughout the studyincluding (but not limited to) general physical appearance and behavior,abnormalities of food and water consumption, vomiting/regurgitation,appearance of urine and feces and any sign of MF anaphylaxis.

The Heterocyclic Compounds provided herein were tested and showedactivity, or will be shown to have activity, on circulatingmicrofilariae in vivo.

Activity Table

Each of the compounds in Table 1 was tested in at least one of the invitro filarial motility assays and was found to have activity therein,with all of the Heterocyclic Compounds of formula (I), formula (Ia),formula (Ib), formula (Ic), formula (II) and formula (IIa) having anIC₅₀ below or 5 μM in one or more of the assays, with some compoundshaving an IC₅₀ or MED between 0.5 μM and 5 μM (activity level A), somehaving an IC₅₀ between 0.2 μM and 0.5 μM (activity level B), and somehaving an IC₅₀ below 0.2 μM (activity level C). Heterocyclic Compoundsof formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II)and formula (IIa) were tested in one or more of the assays and wereshown to have activity therein, with some of the Heterocyclic Compoundsof formula (I), formula (Ia), formula (Ib), formula (Ic), formula (II)or formula (IIa) having activity against microfilaria at compoundconcentrations below 1 μM (activity level D) with some compounds havingactivity against adult filaria at compound concentrations below 1 μM(activity level E).

TABLE 1 O. L. B. D. Cmpd guttu- B. sigmo- paha- immit- No. StructureName M + 1 rosa malayi dontis ngi is  1

3-(pyridin-2- yl)-N-(5- trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5- amine 324.2 C D, E C  2

N-(5-methoxy- pyridin-2-yl)- 3-(pyridin-2- yl)-1,2,4- thiadiazol-5-amine 286.2 A D, E E A  3

3-(pyridin-2- yl)-N-(5- (trifluoromethyl) pyridin-3- yl)-1,2,4-thiadiazol-5- amine 324.2 A D, E A  4

N-(5-(piperazin- 1-yl)pyridin- 2-yl)-3-(pyridin- 2-yl)-1,2,4-thiadiazol-5- amine 340.2 A E  5

N-(5-morpholino- pyridin-2- yl)-3-(pyridin- 2-yl)-1,2,4- thiadiazol-5-amine 341.2 A D, E  6

N-(5-(piperidin- 1-yl)pyridin- 2-yl)-3-(pyridin- 2-yl)-1,2,4-thiadiazol-5- amine 329.2 C D, E A  7

N-(5-(4-methyl- piperazin-1- yl)pyridin-2-yl)- 3-(pyridin-2- yl)-1,2,4-thiadiazol-5- amine 354.2 D, E  8

3-(pyridin-2- yl)-N-(5- (pyrrolidin-1- yl)pyridin-2- yl)-1,2,4-thiadiazol-5- amine 325.2 C D, E D, E A  9

3-(pyridin- 2-yl)-N-(5- (tetrahydro- 2H-pyran-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 356.2 A D D, E A  10

N-(5-(piperidin-4- yloxy)pyridin- 2-yl)-3- (pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 355.2 A D  11

N-(5-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-3- (pyridin-2-yl)-1,2,4- thiadiazol-5- amine 288.1 A D  12

N-(3-fluoropyridin- 2-yl)-3- (4-methylpyridin- 2-yl)-1,2,4-thiadiazol-5- amine 288 C D, E D, E B  13

N-(4-methyl- pyridin-2-yl)-3- (3-(trifluoro- methyl)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 338.1 A D, E D, E  14

N-(3-fluoro- pyridin-2-yl)-3- (4-methylpyridin- 2-yl)-1,2,4-oxadiazol-5- amine 272.1 A D, E D, E A  15

N-(3-methyl- pyridin-2-yl)-3- (5-(tetrahydro- 2H-pyran-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 370.2 C D, E D, E A  16

N-(3-methyl- pyridin-2-yl)-3- (5-(tetrahydro- 2H-pyran-4- yloxy)pyridin-2-yl)-1,2,4- oxadiazol-5- amine 354.2 C D, E D, E A  17

N,N-dimethyl- 6-(5-(3- methylpyridin- 2-ylamino)- 1,2,4-thiadiazol-3-yl)nicotinamide 341.1 C D, E D  18

3-(5-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N-(3- methylpyridin-2-yl)-1,2,4- thiadiazol-5- amine 383.3 B D, E D, E E  19

3-(5-isopropoxy- pyridin-2-yl)- N-(3-methyl- pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 328.2 C D, E D, E E C  20

3-(5-isopropoxy- pyridin-2-yl)- N-(3-methyl- pyridin-2-yl)-1,2,4-oxadiazol- 5-amine 312.1 C D, E D A  21

3-(5-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N-(3- methylpyridin-2-yl)-1,2,4- oxadiazol-5- amine 367.2 C D, E D  22

N,N-dimethyl- 2-(5-(3- methylpyridin- 2-ylamino)- 1,2,4-thiadiazol-3-yl)isonicotinamide 341.3 A D, E D  23

N3-methyl- N2-(3-(4- methylpyridin- 2-yl)-1,2,4- thiadiazol-5-yl)pyridine-2,3- diamine 299.3 C D, E D, E E B  24

N-(3-methoxy- pyridin-2-yl)- 3-(4-methyl- pyridin-2-yl)-1,2,4-thiadiazol- 5-amine 300.1 C D, E D  25

N-(5-ethoxy- pyridin-2-yl)-3- (3-fluoropyridin- 2-yl)-1,2,4-oxadiazol-5-amine 302.1 C D  26

4-(6-(5-((3- methylpyridin-2- yl)amino)-1,2,4- thiadiazol-3-yl)pyridin-3- yl)thio- morpholine 1,1- dioxide 403 A D  27

3-(3-fluoropyridin- 2-yl)-N- (4-(trifluoro- methyl)pyridin-2- yl)-1,2,4-oxadiazol-5-amine 326.1 C E D  28

3-(pyridin-2- yl)-N-(4- (trifluoro- methyl)pyridin-2- yl)-1,2,4-oxadiazol-5-amine 306.1 C D D E  29

N-(6-(5-(3-methyl pyridin-2- ylamino)-1,2,4- thiadiazol-3-yl)pyridin-3-yl) acetamide 327.1 B D E  30

N-(3-fluoro- pyridin-2-yl)-3- (5-(1-methyl- piperidin-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 387.1 C E E  31

N,N-dimethyl- 6-(5-(3- methylpyridin- 2-ylamino)- 1,2,4- thiadiazol-3-yl)pyridine-3- sulfonamide 337.1 A D E  32

5-(3-methyl- pyridin-2-yl)-N- (pyridin-2-yl)- 1,3,4- oxadiazol-2- amine254.1 A E  33

N,3-di(pyridin- 2-yl)-1,2,4- thiadiazol-5- amine 256.1 C D, E D E  34

3-(5-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N-(4- (trifluoro-methyl)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 437.1 A D, E D E  35

N-(5-ethoxy- pyridin-2-yl)-3- (4-methoxy- pyridin-2-yl)- 1,2,4-oxadiazol-5- amine 314.1 C D D E  36

3-(5-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N- (pyrimidin-2-yl)-1,2,4- thiadiazol- 5-amine 370.2 A D E  37

3-(4-methyl- pyridin-2-yl)-N- (3-(trifluoro- methyl)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 338.1 C D, E D, E E  38

3-(5-cyclo- propoxypyridin-2- yl)-N-(3-methyl- pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 326.1 C D, E D, E E B  39

3-(5-(1-methyl- piperidin-4- yloxy)pyrimidin- 2-yl)-N-(3-methylpyridin-2- yl)-1,2,4- thiadiazol-5- amine 384.2 E E  40

2-(5-(3-methyl- pyridin-2- ylamino)-1,2,4- thiadiazol-3- yl)isonicotino-nitrile 295.2 A D D, E E A  41

N-(5-(3-methyl- pyridin-2-yl)- 4H-1,2,4-triazol- 3-yl)pyridin- 2-amine253.2 C D, E D, E  42

3-(3-methyl- pyridin-2-yl)-N- (5-(pyrrolidin- 1-yl)pyridin-2- yl)-1,2,4-oxadiazol-5-amine 323.3 C E D A  43

3-(5-methoxy- pyridin-2-yl)- N-(5-(tetrahydro- 2H-pyran-4-yloxy)pyridin- 2-yl)-1,2,4- thiadiazol-5- amine 386.1 C D, E E  44

3-(4-(1-methyl- piperidin-4- yl)pyridin-2- yl)-N-(3- methylpyridin-2-yl)-1,2,4- thiadiazol-5- amine 367.1 C E E  45

3-(5-(1-cyclo- propylpiperidin- 4-yloxy)pyridin- 2-yl)-N-(3-methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 409.2 C E D, E E A  46

3-(5-methoxy- pyridin-2-yl)- N-(4-(tetrahydro- 2H-pyran-4-yloxy)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 386.1 B D, E  47

3-(5-methoxy- pyridin-2-yl)- N-(4-(tetrahydro- 2H-pyran-4-yloxy)pyridin-2- yl)-1,2,4- oxadiazol-5- amine 370.2 A D  48

3-(5-(1-methyl- piperidin-4- yl)pyridin-2-yl)- N-(3- methylpyridin-2-yl)-1,2,4- thiadiazol-5- amine 367.2 A D, E  49

N-(5-(1-methyl- piperidin-4- yl)pyridin-2- yl)-3-(3- methylpyridin-2-yl)-1,2,4- thiadiazol-5- amine 367.2 A  50

3-(5-methoxy- pyridin-2-yl)- N-(5-(1-methyl- piperidin-4- yl)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 383.1 A  51

3-(3-methyl- pyridin-2-yl)-N- (5-(pyrrolidin-1- yl)pyridin-2- yl)-1,2,4-thiadiazol-5- amine 339.1 C D D, E E A  52

N-(3-methyl- pyridin-2-yl)-3- (5-(trifluoro- methoxy)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 354.1 C D D E A  53

N3-methyl- N2-(3-(5-(1- methyl- piperidin-4- yloxy)pyridin- 2-yl)-1,2,4-thiadiazol-5-yl) pyridine-2,3- diamine 398.3 B D D  54

3-(5-isopropoxy- pyridin-2-yl)- N-(3- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 382.2 C D, E D, E E C  55

3-(5-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N-(3-(trifluoromethyl) pyridin-2- yl)-1,2,4- thiadiazol-5- amine 437.1 C D D,E E A  56

N2-(3-(5-isoprop- oxypyridin- 2-yl)-1,2,4- thiadiazol-5-yl)- N3,N3 -dimethyl- pyridine-2,3- diamine 357.1 A D, E D, E E B  57

(4-methyl- piperazin-1-yl)(6- (5-(3-methyl- pyridin-2- ylamino)-1,2,4-thiadiazol-3- yl)pyridin-3-yl) methanone 396.1 A D E  58

(6-(5-(3-methyl- pyridin-2- ylamino)-1,2,4- thiadiazol-3- yl)pyridin-3-yl)(morpholino) methanone 383.1 B E  59

N3,N3-dimethyl- N2-(3-(5-(1- methylpiperidin-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- yl)pyridine-2,3- diamine 412.2 A  60

6-(5-(3-methyl- pyridin-2- ylamino)-1,2,4- thiadiazol-3- yl)-N-(2,2,2-trifluoroethyl) nicotinamide 395.1 A D E  61

(6-(5-(3-methyl- pyridin-2- ylamino)-1,2,4- thiadiazol-3-yl)pyridin-3-yl) (pyrrolidin-1- yl)methanone 367.2 B  62

3-(4-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N-(3-(trifluoromethyl) pyridin-2- yl)-1,2,4- thiadiazol-5- amine 437.1 C D DE A  63

5-(5-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N-(3- methylpyridin-2-yl)-1,3,4- thiadiazol-2- amine 383.1 A E  64

5-(5-isopropoxy- pyridin-2-yl)- N-(3-methyl- pyridin-2-yl)- 1,3,4-thiadiazol-2- amine 328.2 A E  65

3-(4-cycloprop- oxypyridin-2- yl)-N-(3-methyl- pyridin-2-yl)-1,2,4-thiadiazol- 5-amine 326.1 A D, E E E C  66

N-(5-isopropyl-4- (trifluoromethyl) pyridin-2- yl)-3-(5-methoxy-pyridin-2- yl)-1,2,4- thiadiazol-5- amine 396.1 B D E E  67

3-(4-isopropyl- pyridin-2-yl)- N-(3- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 366.1 C D, E E E C  68

N-(5-cyclopentyl- pyridin-2- yl)-3-(5- methoxypyridin-2- yl)-1,2,4-thiadiazol-5- amine 354.1 B D, E E E A  69

N-(3-(5- isopropoxy- pyridin-2- yl)-1H-1,2,4- triazol-5-yl)-3-methylpyridin- 2-amine 311.3 B D, E  70

N-(3-(5- isopropoxy- pyridin-2- yl)-1H-1,2,4- triazol-5-yl)-3-(trifluoromethyl) pyridin-2- amine 365.1 A A  71

3-methyl-N- (3-(5-(1- methyl- piperidin-4- yloxy)pyridin-2-yl)-1H-1,2,4- triazol-5-yl) pyridin-2-amine 365.1 A  72

3-(5-(1-cyclo- pentylpiperidin- 4-yloxy)pyridin- 2-yl)-N-(3-methylpyridin-2- yl)-1,2,4- thiadiazol-5-amine 365.1 B D D D  73

3-(5- (cyclopropyl- methoxy)pyridin- 2-yl)-N-(3- methylpyridin-2-yl)-1,2,4- thiadiazol-5- amine 340.1 C D, E D, E D, E B  74

3-(5-cyclopropoxy- pyridin-2- yl)-N-(3- isopropylpyridin-2- yl)-1,2,4-thiadiazol-5- amine 354.2 C D, E D, E D, E C  75

3-(5-(1- (cyclopropyl- methyl)piperidin- 4-yloxy) pyridin-2-yl)- N-(3-methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 423.1 B D D, E D, E  76

N-(3-cyclopropyl- pyridin-2- yl)-3-(5- isopropoxy- pyridin-2- yl)-1,2,4-thiadiazol-5- amine 354.1 C D, E D, E D, E C  77

3-(5-(6- methyl-6- azaspiro [3.4]octan-2- yloxy)pyridin- 2-yl)-N-(3-methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 409.2 A D D, E D, E  78

N2-(3-(5- cyclopropoxy- pyridin-2-yl)- 1,2,4-thiadiazol- 5-yl)-N3,N3-dimethyl- pyridine-2,3- diamine 355.2 A D, E D, E D, E A  79

N-(3-methyl- pyridin-2-yl)-3- (5-(methyl- sulfonyl)pyridin-2- yl)-1,2,4-thiadiazol-5-amine 348.1 A D  80

3-(5-cycloprop- oxypyridin-2- yl)-N-(3- methoxypyridin-2- yl)-1,2,4-thiadiazol-5-amine 342.1 B D, E D D, E A  81

3-(5-isopropoxy- pyridin-2-yl)- N-(3-methoxy- pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 344.2 C D, E D, E D, E  82

3-(5-(2-cyclo- propyl-2- azaspiro[3.3] heptan-6- yloxy)pyridin-2-yl)-N-(3- methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 421.2 B D, ED, E  83

3-(5-(1-cyclo- propyl-3,3- difluoro- piperidin-4- yloxy)pyridin-2-yl)-N-(3- methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 445.2 B D, ED, E B  84

3-(4-cyclopropyl- pyridin-2- yl)-N-(3- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 364 C D, E D, E C  85

3-(4-cyclopropyl- pyridin-2- yl)-N-(4- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 364 C D, E D, E C  86

3-(4-isopropyl- pyridin-2-yl)- N-(4- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 366.1 C D, E D, E C  87

3-(5-(1-cyclo- propyl-3,3- difluoro- piperidin-4- yloxy)pyridin-2-yl)-N-(3- isopropylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 473.3 CD, E B  88

3-(5-(2- methyl-2- azaspiro[3.3] heptan-6- yloxy)pyridin- 2-yl)-N-(3-methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 395.1 A D  89

3-(5-((3S,4R)-1- cyclopropyl- 3-fluoro- piperidin-4- yloxy)pyridin-2-yl)-N-(3- isopropylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 455.2 C ED, E C  90

3-(5-((3R,4R)-1- cyclopropyl- 3-fluoro- piperidin-4- yloxy)pyridin-2-yl)-N-(3- isopropylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 455.1 C ED, E  91

3-(5-((3R,4R)-1- cyclopropyl- 3-fluoro- piperidin-4- yloxy)pyridin-2-yl)-N-(3- methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 427.2 C E D,E A  92

3-(5-((3S)-1- cyclopropyl-3- fluoro- piperidin-4- yloxy)pyridin-2-yl)-N-(3- methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 427.2 C D, E 93

3-(5-cyclo- propoxy-3- (trifluoromethyl) pyridin-2- yl)-N-(3-methyl-pyridin-2-yl)- 1,2,4-thiadiazol- 5-amine 394 A D, E A  94

3-(3-isopropoxy- pyridin-2-yl)- N-(4- (pyrrolidin-1- yl)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 383.3 C D, E A  95

3-(5-cyclopropoxy- pyridin-2- yl)-N-(5- isopropyl-4- (trifluoromethyl)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 422.1 C D D, E C  96

3-(4-cycloprop- oxypyridin-2- yl)-N-(5- isopropyl-4- (trifluoromethyl)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 422.1 C D D, E C  97

3-(3-cycloprop- oxypyridin-2- yl)-N-(5- isopropyl-4- (trifluoromethyl)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 422.1 C D D, E C  98

3-(5-isopropoxy- pyridin-2-yl)- N-methyl-N-(3- methylpyridin-2-yl)-1,2,4- thiadiazol-5- amine 342.2 B D E  99

N-(4- (pyrrolidin-1- yl)pyridin- 2-yl)-3-(4- (trifluoromethyl)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 393.1 A D E 100

3-(5-(1- methylpiperidin-4- ylsulfonyl) pyridin-2-yl)-N-(3-methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 431.1 B D D 101

N3,N3-dimethyl- N2-(3-(5- (2,2,2- trifluoroethoxy) pyridin-2-yl)-1,2,4-thiadiazol-5- yl)pyridine-2,3- diamine 397 B D D, E 102

3-(5-cyclo- propoxy-4- (trifluoromethyl) pyridin-2- yl)-N-(3-methyl-pyridin-2-yl)- 1,2,4-thiadiazol- 5-amine 394 A D E E B 103

N-(5-(5- cyclopropoxy- pyridin-2-yl)-1- methyl-1H-1,2,4- triazol-3-yl)-3-methyl- pyridin-2-amine 323.3 C 104

5-(4-isopropyl- pyridin-2-yl)- N-(3-methyl- pyridin-2-yl)-1,3,4-oxadiazol- 2-amine 296.3 C E 105

N-(3-methoxy- pyridin-2-yl)- 3-(5-(2,2,2- trifluoroethoxy)pyridin-2-yl)- 1,2,4- thiadiazol-5- amine 384 C D E 106

6-(3-(5-cyclo- propoxypyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)-N-(cyclopropyl- methyl) nicotinamide 409.2 A D E E 107

6-(3-(5-cyclo- propoxypyridin- 2-yl)-1,2,4- thiadiazol-5-ylamino)-N-(3,3- difluoro- cyclobutyl) nicotinamide 445.2 A D E A 108

N2-(3-(5- isopropoxypyridin- 2-yl)-1,2,4- thiadiazol-5-yl)- N3-methyl-pyridine-2,3- diamine 343.1 B D E E B 109

3-(5- cyclopropoxy-4- (trifluoromethyl) pyridin-2- yl)-N-(3- isopropyl-pyridin-2- yl)-1,2,4- thiadiazol-5- amine 422.1 C D E 110

3-(5-(cyclo- propylmethoxy)- 4-(trifluoromethyl) pyridin-2-yl)-N-(3-methyl- pyridin-2-yl)- 1,2,4- thiadiazol-5- amine 408.1 C D D,E E B 111

N2-(3-(5-cyclo- propoxy-4- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5-yl)- N3,N3-dimethyl- pyridine-2,3- diamine 423.1 C D D, E E112

1-(4-(6-(3-(5- cyclopropoxy- pyridin-2-yl)- 1,2,4-thiadiazol-5- ylamino)pyridin-3- yl)piperazin-1-yl) ethanone 438.1 B D D 113

1-(4-(6-(3-(5- cycloprop- oxypyridin-2-yl)- 1,2,4-thiadiazol-5-ylamino)pyridin-3- yl)piperazin- 1-yl)-3,3,3- trifluoro- propan-1-one506.1 A D D 114

3-(6-(cyclo- propylmethyl)- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-2-yl)-N-(3- methylpyridin- 2-yl)-1,2,4- thiadiazol-5- amine 365.2 A 115

3-(5-isopropoxy- pyridin-2-yl)- N-(3-isopropyl- pyridin-2-yl)-1,2,4-thiadiazol- 5-amine 356.2 C D D, E C 116

3-(5-isopropoxy- pyridin-2-yl)- N-(3- (pyrrolidin-1- yl)pyridin-2-yl)-1,2,4- thiadiazol-5- amine 383.1 C D D, E A 117

N2-(3-(3- cycloprop- oxypyridin-2-yl)- 1,2,4-thiadiazol- 5-yl)-N3,N3-dimethyl- pyridine-2,3- diamine 355 B D D, E 118

N2-(3-(5- (cyclopropyl- methoxy)pyridin- 2-yl)-1,2,4- thiadiazol-5-yl)-N3,N3-dimethyl- pyridine-2,3- diamine 369.1 C D D, E A 119

3-(5-isopropoxy- pyridin-2-yl)- N-(5-isopropyl-4- (trifluoromethyl)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 424.1 C D, E D, E 120

N2-(3-(5- (difluoromethoxy) pyridin-2- yl)-1,2,4- thiadiazol-5-yl)-N3,N3-dimethyl- pyridine-2,3- diamine 365.1 A A 121

N2-(3-(5-fluoro- pyridin-2-yl)- 1,2,4-thiadiazol- 5-yl)-N3,N3-dimethylpyridine- 2,3-diamine 317.1 C D, E D, E A 122

N2-(3-(5-(1- cyclopropyl-3,3- difluoropiperidin-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- yl)-N3- methyl- pyridine-2,3- diamine 460.2 BD, E D, E 123

N2-(3-(5-(1- cyclopropyl-3,3- difluoro- piperidin-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- yl)-N3,N3- dimethyl- pyridine-2,3- diamine474.2 C D, E D, E 124

3-(5-isopropoxy- pyrazin-2- yl)-N-(3-methyl- pyridin-2-yl)-1,2,4-thiadiazol- 5-amine 329.1 B D D A 125

3-(5-methoxy- pyrazin-2-yl)- N-(3-methyl- pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 301.1 A D D 126

N2-(3-(5-iso- propoxypyrazin- 2-yl)-1,2,4- thiadiazol-5-yl)- N3,N3-dimethylpyridine- 2,3- diamine 358.2 A E D, E 127

3-(5- (difluoro- methoxy) pyridin-2- yl)-N-(3- isopropyl- pyridin-2-yl)-1,2,4- thiadiazol-5- amine 364 C D, E D A 128

3-(5-fluoro- pyridin-2-yl)-N- (3-isopropyl- pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 316 A D, E D, E 129

3-(5-(1- cyclopropyl-3,3- difluoro- piperidin-4- yloxy)pyridin-2-yl)-N-(3- methoxypyridin- 2-yl)-1,2,4- thiadiazol- 5-amine 461.1 A D D130

3-(5-isopropoxy- pyridin-2-yl)- N-(3-isopropy- lpyridin-2-yl)-N-methyl-1,2,4- thiadiazol-5- amine 370.2 A D D, E 131

N-ethyl-3-(5- isopropoxy- pyridin-2-yl)-N- (3-methyl- pyridin-2-yl)-1,2,4- thiadiazol-5- amine 356.1 C D 132

N2-(5-(5- isopropoxy- pyridin- 2-yl)-1,3,4- oxadiazol-2-yl)- N3,N3-dimethyl- pyridine-2,3- diamine 341.1 C D 133

N2-(3-(5-is- opropoxy- pyridin- 2-yl)-1,2,4- oxadiazol-5-yl)- N3,N3-dimethyl- pyridine-2,3- diamine 341.3 A D 134

3-(5-cyclo- propoxy-4- (trifluoromethyl) pyridin-2- yl)-N-(3- methoxy-pyridin-2- yl)-1,2,4- thiadiazol- 5-amine 410.1 A D, E D, E A 135

3-(5-isoprop- oxypyridin- 2-yl)- N-(3-methyl- pyrazin-2-yl)- 1,2,4-thia-diazol-5-amine 329.1 C D, E D B 136

N2-(3-(5-(3,3- difluorocyclo- butoxy)pyridin- 2-yl)-1,2,4-thiadiazol-5-yl)- N3,N3- dimethyl- pyridine-2,3- diamine 405.1 A D, E D,E 137

3-(5-(3,3- difluorocyclo- butoxy)pyridin- 2-yl)-N-(3- methoxypyridin-2-yl)-1,2,4- thiadiazol-5- amine 392.1 A D, E D A 138

3-(5-isoprop- oxypyridin-2-yl)- N-isopropyl-N-(3- methylpyridin-2-yl)-1,2,4- thiadiazol-5- amine 370.1 A D 139

N2-(3-(5-isoprop- oxypyridin- 2-yl)-1,2,4- thiadiazol-5-yl)- N2,N3,N3-trimethylpyridine- 2,3-diamine 371.1 A D, E D 140

N2-(3-(5-isoprop- oxypyridin- 2-yl)-1H-1,2,4- triazol-5-yl)-N3,N3-dimethyl- pyridine-2,3- diamine 340.2 A D, E D 141

N3,N3-dimethyl- N2-(3-(5-(1- methylazetidin-3- ylsulfonyl)pyridin-2-yl)- 1,2,4- thiadiazol-5- yl)pyridine-2,3- diamine 432.1 A D,E 142

N3,N3-dimethyl- N2-(3-(5-(1- methylpiperidin-4- ylsulfonyl)pyridin-2-yl)- 1,2,4-thiadiazol-5- yl)pyridine- 2,3-diamine 460.2 A D143

5-isopropyl-N- (1-methyl-5- (pyridin-2-yl)- 1H-1,2,4- triazol-3-yl)-4-(trifluoromethyl) pyridin-2- amine 363.1 A D, E 144

N2-(3-(5-isoprop- oxypyridin- 2-yl)-1,2,4- thiadiazol-5-yl)-N3,N3-dimethyl- pyrazine-2,3- diamine 358 B D, E B 145

N2-(3-(5-(1- cyclopropyl- piperidin-4- ylsulfonyl) pyridin-2-yl)-1,2,4-thiadiazol- 5-yl)-N3,N3- dimethyl- pyridine-2,3- diamine 486.1 AD, E 146

N-(5-(4-isoprop- oxypyridin-2- yl)-1-methyl- 1H-1,2,4- triazol-3-yl)-5-isopropyl-4- (trifluoro- methyl) pyridin-2- amine 421.2 A 147

N2-(3-(4-isoprop- oxy-5- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5-yl)- N3,N3- dimethyl- pyridine-2,3- diamine 425.1 A D, E148

N-(5-(3-isoprop- oxypyridin-2- yl)-1-methyl- 1H-1,2,4- triazol-3-yl)-5-isopropyl-4- (trifluoromethyl) pyridin-2- amine 421.2 A D 149

N2-(3-(5- isobutoxy- pyridin-2- yl)-1,2,4- thiadiazol-5-yl)- N3,N3-dimethyl- pyridine-2,3- diamine 371.1 C D, E 150

N2-(3-(5- isobutoxy- pyrazin-2- yl)-1,2,4- thiadiazol-5-yl)- N3,N3-dimethyl- pyridine-2,3- diamine 372.1 A D, E 151

3-(4-cyclo- propoxy-5- (trifluoromethyl) pyridin-2- yl)-N-(3-methylpyridin- 2-yl)- 1,2,4- thiadiazol- 5-amine 394 C E 152

3-(4-isoprop- oxy-5- (trifluoromethyl) pyridin-2- yl)-N-(3-methylpyridin- 2-yl)- 1,2,4-thia- diazol-5-amine 396.1 B E B 153

N2-(3-(4-cyclo- propoxy-5- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5-yl)- N3,N3- dimethyl- pyridine-2,3- diamine 423.1 A E 154

5-(5-isoprop- oxypyridin-2-yl)- N-(5- isopropyl-4- (trifluoro- methyl)pyridin-2- yl)-1,3,4- oxadiazol-2- amine 408.1 B 155

N2-(3-(6- isopropoxy- pyridazin-3-yl)- 1,2,4- thiadiazol-5-yl)- N3,N3-dimethyl- pyridine-2,3- diamine 358.1 A D D, E E A 156

N2-(3-(5- isopropoxy-4- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5-yl)- N3,N3- dimethyl- pyridine-2,3- diamine 425.1 C D D, EE B 157

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- methyl- acetamide 385.2 A D, E D, E D, E A 158

N2-(5-(5- methoxy- pyrazin-2- yl)-1,3,4- oxadiazol- 2-yl)- N3,N3-dimethyl- pyridine-2,3- diamine 314.1 A D, E E 159

N2-(3-(5- isopropoxy- pyridin- 2-yl)-1,2,4- thiadiazol-5-yl)- N2,N3-dimethyl- pyridine-2,3- diamine 357.3 A D, E E 160

N2-(5-(5- isopropoxy-4- (trifluoromethyl) pyridin-2- yl)-1,3,4-oxadiazol-2-yl)- N3,N3- dimethyl- pyridine-2,3- diamine 409.3 A D E 161

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3- yl)acetamide 371.3 A D D, E E A 162

N3,N3- dimethyl- N2-(3-(1- methyl-2,3- dihydro-1H- pyrrolo[2,3-c]pyridin-5-yl)- 1,2,4- thiadiazol-5- yl)pyridine-2, 3-diamine 354.3 C DD, E E 163

N3,N3-dimethyl- N2-(3-(2- methyl-2,3- dihydro-1H- pyrrolo[3,4-c]pyridin-4-yl)- 1,2,4-thia- diazol-5- yl)pyridine-2,3- diamine 354.3 C DD, E E 164

2-(3-(5-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)nicotinamide 357.3 A D, E E 165

3-(5-isopropoxy- pyridin-2-yl)- N-(5-isopropyl-3- (trifluoromethyl)pyridin-2- yl)-1,2,4- thiadiazol-5- amine 424.2 C D D, E E 166

3-(5-isopropoxy- pyridin-2-yl)- N-(5- isopropyl-3- methoxypyridin-2-yl)-1,2,4- thiadiazol-5- amine 386.3 C D D, E E A 167

3-(5- isopropoxy-4- (trifluoromethyl) pyridin-2- yl)-N-(3-methoxypyridin-2- yl)-1,2,4- thiadiazol-5- amine 412.1 B D D, E E A 168

3-(5-isoprop- oxy-4- (trifluoromethyl) pyridin-2- yl)-N-(3-isopropyl-pyridin-2- yl)-1,2,4- thiadiazol-5- amine 424.2 C D D, E E B 169

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- methyliso- butyramide 413.2 B D, E D, E E 170

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- methylcyclo- propanecarbox- amide 411.2 B D, E D, E D,E A 171

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- methylcyclo- butane- carboxamide 425.2 C D D E A 172

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- methylcyclo- pentane- carboxamide 439.2 C D, E D, E E B173

5-(4-isopropoxy- pyridin-2-yl)- N-(3-methyl- pyridin-2-yl)- 1,3,4-thia-diazol-2-amine 328.1 A E E 174

5-(4-methoxy- pyridin-2-yl)- N-(5- (trifluoromethyl) pyridin-2-yl)-1,3,4- thiadiazol-2- amine 354 B D E 175

5-(4-isopropoxy- pyridin-2-yl)- N-(5-methoxy- pyridin-2-yl)- 1,3,4-thiadiazol-2- amine 344.1 D 176

3-(4-methoxy- pyridin-2-yl)- N-(5- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 354 C D, E D, E E C 177

N-(5-isopropyl- pyridin-2-yl)- 3-(4-methoxy- pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 328 C D, E D, E C 178

1-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3- yl)pyrrolidin- 2-one 397.2 A D, E D E A 179

1-(2-(3-(5- isopropoxy-4- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5- ylamino) pyridin-3- yl)pyrrolidin- 2-one 465.2 A D, E D, EE A 180

5-(5-isopropoxy- pyridin-2-yl)- N-(5-methoxy- pyridin-2-yl)- 1,3,4-oxadiazol-2- amine 328.2 A D 181

5-(5-isopropoxy- pyridin-2-yl)- N-(5-isopropyl- pyridin-2-yl)- 1,3,4-thiadiazol-2- amine 355.8 A D 182

N-(5-iso- propyl-4- (trifluoro- methyl)pyridin-2- yl)-3-(4- methoxy-pyridin-2- yl)-1,2,4- thiadiazol-5- amine 395.8 B D D, E D C 183

3-(4-(cyclo- hexyloxy) pyridin- 2-yl)-N-(5- methoxypyridin- 2-yl)-1,2,4-thiadiazol-5- amine 384.1 B D D, E D C 184

N-(5-isoprop- oxypyridin-2- yl)-3-(4- methoxy- pyridin-2- yl)-1,2,4-thiadiazol-5- amine 343.9 C D D, E D, E 185

N-(5-isopropyl- pyridin-2-yl)- 3-(5-methoxy- pyridin-2-yl)- 1,2,4-thiadiazol-5- amine 328 B D D, E D, E 186

N-(2-(3-(5- isopropoxy-4- (trifluoro- methyl) pyridin-2- yl)-1,2,4-thiadiazol-5- ylamino) pyridin-3-yl)-N- methylcyclo- propanecarbox-amide 479.1 A E D, E D, E B 187

N-(2-(3-(5- isopropoxy-4- (trifluoro- methyl)pyridin- 2- yl)-1,2,4-thiadiazol-5- ylamino) pyridin-3- yl)-N- methylacetamide 453.1 A D, E D,E D, E B 188

2-(3-(5-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-N,N-dimethyl nicotinamide 385.2 B D D, E D A 189

2-(3-(5-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-N-methyl- nicotinamide 371.1 A D, E 190

(2-(3-(5-isoprop- oxypyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)pyridin-3- yl) (pyrrolidin-1- yl) methanone 411.3 B D D, E D, E A 191

N-(3,3-difluoro- cyclobutyl)-2- (3-(5-isoprop- oxypyridin-2- yl)-1,2,4-thiadiazol-5- ylamino)-N- methyl- nicotinamide 461.3 B D D, E D, E A 192

5-isopropoxy- N,N-dimethyl- 2-(5-(3- methylpyridin-2- ylamino)- 1,2,4-thiadiazol-3- yl)isonicotin- amide 399.3 A D 193

5-isopropoxy- 2-(5-(3- isopropylpyridin- 2-ylamino)- 1,2,4-thiadiazol-3-yl)-N,N- dimethy- lisonicotinamide 427.3 B D D D, E 194

5-isopropoxy- N,N-dimethyl- 2-(5-(3-(2- oxopyrrolidin-1- yl)pyridin-2-ylamino)- 1,2,4- thiadiazol-3- yl)isonicotin- amide 468.3 A D, E E 195

N-(3,3-difluoro- cyclobutyl)-6- (3-(5-isoprop- oxypyridin-2- yl)-1,2,4-thiadiazol-5- ylamino)-5- isopropyl- nicotinamide 489.3 C D D, E D, E A196

methyl 5- isopropoxy- 2-(5-(3- methylpyridin- 2-ylamino)- 1,2,4-thiadiazol-3- yl)isonicotinate 386.3 B D, E D, E B 197

methyl 5- isopropoxy- 2-(5-(3- isopropylpyridin- 2-ylamino)- 1,2,4-thiadiazol-3- yl)isonicotinate 414.3 C D, E E E C 198

5-isopropoxy- 2-(5-(3- isopropylpyridin- 2-ylamino)- 1,2,4-thiadiazol-3- yl)isonicotin- amide 399.3 A D, E D, E E A 199

N-methyl- N-(2-(3-(5- (tetrahydro- 2H-pyran-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- ylamino)pyridin- 3-yl)acetamide 427.2 A E E200

5-isopropoxy- 2-(5-(3- methylpyridin- 2-ylamino)- 1,2,4- thiadiazol-3-yl)isonicotino- nitrile 353.3 A D, E E E B 201

5-isopropoxy- 2-(5-(3- isopropyl- pyridin-2- ylamino)- 1,2,4-thiadiazol-3- yl)isonicotino- nitrile 381.3 A D, E E E C 202

N-methyl-N- (2-(3-(1-methyl- 2,3-dihydro- 1H-pyrrolo[2,3- c]pyridin-5-yl)-1,2,4- thiadiazol-5- ylamino)pyridin- 3-yl)acetamide 382.2 B D, E D,E E A 203

N-(2-(3-(5- (3,3-difluoro-1- isopropyl- piperidin-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- ylamino)pyridin- 3-yl)-N- methylacetamide504.3 A D, E E E A 204

1-(2-(3-(5- (bicyclo [1.1.1] pentan-1- ylamino) pyridin-2-yl)- 1,2,4-thiadiazol-5- ylamino)pyridin- 3-yl)pyrrolidin- 2-one 420.3 A D, E E E A205

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- isopropy- lacetamide 413.3 A E E A 206

N-(2-(3- (1-isopropyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4- thiadiazol-5- ylamino)pyridin- 3-yl)-N- methylacetamide 410.3A E D, E E C 207

N-(2-(3-(5- (bicyclo [1.1.1] pentan-1- ylamino) pyridin-2-yl)- 1,2,4-thiadiazol-5- ylamino)pyridin- 3-yl)-N- methylacetamide 408.3 A E E A208

N-methyl-N- (2-(3-(4- methylpyridin-2 -yl)-1,2,4- thiadiazol-5-ylamino)pyridin- 3-yl)acetamide 341.3 A D, E E A 209

3-(5-methoxy- pyridin-2-yl)- N-(5- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 354.3 C D, E A 210

N-(5- isopropyl-4- (trifluoromethyl) pyridin-2- yl)-3-(3- methoxy-pyridin-2- yl)-1,2,4- thiadiazol-5- amine 396 B D, E B 211

5-(4-isopropoxy- pyridin-2-yl)- N-(3-methyl- pyridin-2-yl)- 1,3,4-oxadiazol-2- amine 312.3 A 212

5-(4-isoprop- oxypyridin- 2-yl)- N-(5-methoxy- pyridin-2-yl)- 1,3,4-oxadiazol-2- amine 328.1 A 213

3-(4-(cyclo- hexyloxy) pyridin- 2-yl)-N-(5- (trifluoromethyl) pyridin-2-yl)-1,2,4- thiadiazol-5- amine 422.1 C C 214

5-(4-(cyclohexy- loxy)pyridin- 2-yl)-N-(5- methoxypyridin- 2-yl)-1,3,4-oxadiazol-2- amine 368.2 C 215

N-(5-isoprop- oxypyridin-2- yl)-3-(5- methoxy- pyridin-2- yl)-1,2,4-thiadiazol-5- amine 344.1 A A 216

N-(2-(3-(4-iso- propylpyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- methyl- acetamide 369.1 B E E D, E B 217

N-(2-(3-(4- isopropylpyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)pyridin-3-yl)-N- methylcyclo- propanecarbox- amide 395.3 B E E D, E A218

5-isopropoxy- N,N-dimethyl- 2-(5-(3- (trifluoromethyl) pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)isonico- tinamide 453.1 A E E D, E A219

5-isopropoxy- 2-(5-(5- isopropyl-3- (trifluoromethyl) pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)-N,N- dimethyliso- nicotinamide 495.3 BE E D, E B 220

5-isopropoxy- 2-(5-(3- (trifluoromethyl) pyridin-2- ylamino)-1,2,4-thiadiazol-3- yl)isonico- tinamide 425.1 B E E E A 221

5-isopropoxy- 2-(5-(5- isopropyl-3- (trifluoromethyl) pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)iso- nicotinamide 467.3 B E E E B 222

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- oxadiazol-5- ylamino)pyridin-3-yl)-N- methyl- acetamide 369.3 A 223

N-(2-(3-(4- isopropyl-5- methylpyridin- 2-yl)-1,2,4- thiadiazol-5-ylamino)pyridin- 3-yl)-N- methyl- acetamide 383.3 B E E D, E B 224

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- oxadiazol-5- ylamino)pyridin-3-yl)-N- methylcyclo- propanecarbox- amide 395.3 E 225

2-(3-(5- isopropoxy-4- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5- ylamino)-N,N- dimethyl- nicotinamide 453.3 A E D, E D, E226

N-(2-(3-(4- cyano-5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5-ylamino) pyridin-3-yl)-N- methyl- acetamide 410.3 A E D, E 227

N-(2-(3-(4- cyano-5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5-ylamino) pyridin-3-yl)-N- methylcyclo- propanecarbox- amide 436.2 E D228

N-(2-(3-(5- ethoxy-4- (trifluoro- methyl)pyridin-2- yl)-1,2,4-thiadiazol-5- ylamino) pyridin-3-yl)-N- methyl- acetamide 439.2 E E E A229

N,N-dimethyl- 2-(3-(1- methyl-2,3- dihydro-1H- pyrrolo[2,3-c]pyridin-5-yl)- 1,2,4- thiadiazol-5- ylamino) nicotinamide 382.2 A E D, E230

4-isopropyl-N,N- dimethyl-6- (5-(3-methyl- pyridin-2- ylamino)-1,2,4-thiadiazol-3- yl)nicotinamide 383.3 A E E 231

6-(3-(5-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-methyl- nicotinonitrile 353.3 B E E B 232

5-(4-isopropoxy- pyridin-2-yl)- N-(5-isopropyl- pyridin-2-yl)- 1,3,4-thiadiazol-2- amine 356.1 A 233

5-(4-(cyclo- hexyloxy)pyridin- 2-y1)-N-(5- methoxypyridin- 2-yl)-1,3,4-thiadiazol-2- amine 384.1 C D D, E 234

5-(4-(1-methyl- piperidin-4- yloxy)pyridin- 2-yl)-N-(3- methylpyridin-2-yl)-1,3,4- thiadiazol-2- amine 384.2 D 235

N-(4-phenyl- pyridin-2-yl)-5- (pyridin-2- yl)-1,3,4- oxadiazol- 2-amine316.1 A D 236

5-(3-methyl- pyridin-2-yl)-N- (4-methy- lpyridin-2- yl)-1,3,4-oxadiazol- 2-amine 268.1 A D 237

N-(4-phenyl- pyridin-2-yl)-3- (pyridin-2- yl)-1,2,4- thiadiazol- 5-amine332.1 A D, E D B 238

3-(3-methyl- pyridin-2-yl)-N- (4-methyl- pyridin-2-yl)- 1,2,4-thiadiazol- 5-amine 283.9 C D, E D B 239

3-(3-methyl- pyridin-2-yl)-N- (4-methyl- pyridin-2-yl)- 1,2,4-oxadiazol-5- amine 268 C D D A 240

N-(4-pheny- lpyridin-2-yl)-5- (pyridin-2- yl)-1,3,4- thiadiazol-2- amine332 A D 241

4-phenyl-N- (5-(pyridin-2-yl)- 4H-1,2,4- triazol-3-yl) pyridin- 2-amine315.2 C D, E D B 242

4-methyl- N-(5-(3- methyl- pyridin-2- yl)-4H- 1,2,4-triazol-3-yl)pyridin-2- amine 267.3 A D D B 243

N-(4-isoprop- oxypyridin-2- yl)-5-(5- methoxy- pyridin-2- yl)-1,3,4-thiadiazol-2- amine 344.3 A D 244

5-(3-methyl- pyridin-2-yl)-N- (4-methyl- pyridin-2-yl)- 1,3,4-thiadiazol-2- amine 284.3 A D 245

N-(4-isoprop- oxypyridin-2- yl)-3-(5-methoxy- pyridin-2- yl)-1,2,4-thiadiazol-5- amine 344.1 A D, E D B 246

N-(4-phenyl- pyridin-2- yl)-3- (pyridin-2- yl)-1,2,4- oxadiazol-5- amine316 A A 247

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4-thiadiazol- 5-ylamino)-5-(trifluoro- methyl)pyridin-3- yl)-N- methylacetamide 453.3 C E D, E D,E C 248

N-(2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)-5-(trifluoro- methyl)pyridin-3- yl)-N- methylcyclo- propanecarbox- amide479.2 A E E C 249

N-methyl-N- (2-(3-(1-methyl- 2,3-dihydro- 1H-pyrrolo[2,3- c]pyridin-5-yl)-1,2,4- thiadiazol-5- ylamino)-5- (trifluoromethyl) pyridin-3-yl)acetamide 450.2 B E D, E D, E C 250

2-(3-(5-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-N,N-dimethyl-5- (trifluoromethyl) nicotinamide 453.1 A D, E E C 251

(2-(3-(5- isopropoxy-4- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5- ylamino) pyridin-3- yl) (pyrrolidin-1- yl)methanone 479.3A D, E E A 252

5-isopropoxy- 2-(5-(5-methyl- 3-(trifluoro- methyl)pyridin-2- ylamino)-1,2,4- thiadiazol-3- yl)isonico- tinamide 439.2 A D, E E A 253

5-isopropoxy- 2-(5-(5- methoxy-3- (trifluoro- methyl)pyridin-2-ylamino)- 1,2,4- thiadiazol-3- yl)isonico- tinamide 455.1 A D, E E A 254

5-isopropoxy- N,N-dimethyl- 2-(5-(5- methyl-3- (trifluoromethyl)pyridin-2- ylamino)-1,2,4- thiadiazol-3- yl)isonico- tinamide 467.3 A D,E E A 255

N-(4-isoprop- oxypyridin-2- yl)-5-(5- methoxy- pyridin-2- yl)-1,3,4-oxadiazol-2-amine 328 A D 256

N-(4-isoprop- oxypyridin-2- yl)-3-(5- methoxy- pyridin-2- yl)-1,2,4-oxadiazol-5- amine 328.1 D E 257

4-isopropoxy- N-(5-(5- methoxy- pyridin-2- yl)-4H- 1,2,4-triazol-3-yl)pyridin-2- amine 327.3 A D D A 258

3-methyl-N- (5-(5- (tetrahydro- 2H-pyran-4- yloxy)pyridin-2-yl)-4H-1,2,4- triazol-3-yl) pyridin-2-amine 353.2 C D 259

N-(3-methyl- pyridin-2-yl)-5- (5-(tetrahydro- 2H-pyran-4- yloxy)pyridin-2-yl)- 1,3,4- thiadiazol-2- amine 370.2 D 260

2-(3-(4- (difluoro- methyl)-5- isopropoxy- pyridin-2-yl)-1,2,4-thiadiazol- 5-ylamino)- N,N-dimethyl- nicotinamide 435.3 A D D, EB 261

N-(2-(3-(4- (difluoromethyl)- 5-isopropoxy- pyridin-2-yl)- 1,2,4-thiadiazol-5- ylamino) pyridin-3-yl)-N- methylacetamide 435.3 A E D, ED, E B 262

N-cyclo- propyl-2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5-ylamino)- N-methyl- nicotinamide 411.3 A D D D, E B 263

N-cyclo- propyl-2-(3-(5- isopropoxy-4- (trifluoro- methyl)pyridin-2-yl)-1,2,4- thiadiazol-5- ylamino)-N- methyl- nicotinamide 479.3 A D D, ED, E C 264

5-isopropoxy- 2-(5-(5- methoxy-3- (trifluoro- methyl)pyridin-2-ylamino)-1,2,4- thiadiazol-3- yl)-N,N- dimethyliso- nicotinamide 483.1 AD, E D D, E B 265

2-methyl-1- (4-(6-(5-(3- methylpyridin- 2-ylamino)- 1,2,4- thiadiazol-3-yl)pyridin- 3-yloxy) piperidin-1- yl)propan-1-one 439.2 A D, E D, E D, EA 266

1-(4-(6-(5- (3-methyl- pyridin- 2-ylamino)- 1,2,4-thiadiazol-3-yl)pyridin-3- yloxy) piperidin-1- yl)ethanone 411.1 A E E A 267

1-(5-(5-(3- (trifluoromethyl) pyridin-2- ylamino)-1,2,4- thiadiazol-3-yl)-2,3- dihydro-1H- pyrrolo[2,3-c] pyridin-1- yl)ethanone 407.1 A E ED, E B 268

N-(2-(3-(5- isopropoxy-4- (trifluoromethyl) pyridin-2- yl)-1,2,4-thiadiazol-5- ylamino)-5- (trifluoromethyl) pyridin-3- yl)-N-methylacetamide 521.2 A E D, E D, E C 269

N-methyl-N- (6-(5-(3- methylpyridin- 2-ylamino)- 1,2,4-thiadiazol-3-yl)pyridin- 3-yl)acetamide 341.2 D, E D, E E A 270

N-methyl-N- (4-methyl-6-(5- (3-methylpyridin- 2-ylamino)-1,2,4-thiadiazol- 3-yl)pyridin- 3-yl)acetamide 355.2 A D, E D, E E 271

N-(2-(3-(2,2- dimethyl-2,3- dihydrofuro [2,3-c]pyridin-5- yl)-1,2,4-thiadiazol-5- ylamino) pyridin-3-yl)-N- methylacetamide 397.2 A D, E DD, E A 272

N-(2-(3-(2,2- dimethyl-2,3- dihydrofuro [2,3-c]pyridin-5- yl)-1,2,4-thiadiazol-5- ylamino)-5- (trifluoromethyl) pyridin-3- yl)-N-methylacetamide 465.1 B D, E D, E D, E C 273

N-(2-(3-(1- isopropyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4- thiadiazol-5- ylamino)-5- (trifluoromethyl) pyridin-3- yl)-N-methylacetamide 478.2 B D, E D, E D, E C 274

N-(5-(difluoro- methyl)-2-(3- (5-isoprop- oxypyridin-2-yl)- 1,2,4-thiadiazol-5- ylamino) pyridin-3-yl)-N- methylacetamide 435.1 A D, E D,E E A 275

N-(5-methyl-3- (trifluoromethyl) pyridin-2- yl)-3-(4- (oxetan-3-yloxy)pyridin- 2-yl)-1,2,4- thiadiazol-5- amine 410 A D, E D, E D, E C276

methyl 2-(3-(5- isopropoxy- pyridin-2-yl)- 1,2,4- thiadiazol-5- ylamino)nicotinate 372.1 A D, E D, E D, E A 277

N,N-dimethyl- 6-(5-(3- methylpyridin- 2-ylamino)- 1,2,4- oxadiazol-3-yl)nicotinamide 325.2 A 278

6-(5-(3- methylpyridin-2- ylamino)-1,2,4- thiadiazol-3-yl)nicotinonitrile 295.1 A 279

N-(6-(3-(3- isopropoxy- pyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoro- methyl)pyridin- 3-yl)-N- methylacetamide 453.1 A D, E 280

N-(2-(3-(3,3- dimethyl-2-oxo- 2,3-dihydro- 1H-pyrrolo[2,3-c]pyridin-5-yl)- 1,2,4-thiadiazol- 5-ylamino)-5- (trifluoromethyl)pyridin-3-yl)- N-methylacetamide 478.1 A D 281

2-(3-(3-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-N,N-dimethyl-5- (trifluoromethyl) nicotinamide 453.1 A D, E 282

N-methyl-N-(5- (trifluoromethyl)- 2-(3-(1,3,3- trimethy1-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol-5-ylamino)pyridin- 3-yl)acetamide 478.2 D, E 283

N-(2-(3-(2,2- dimethyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4-thiadiazol- 5-ylamino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 464.1 D, E 284

N-(3-(azetidin-1- ylsulfonyl) pyridin-2-yl)- 3-(4- (cyclohexyloxy)pyridin-2-yl)- 1,2,4- thiadiazol-5-amine 473.3 D, E 285

N-(6-(3-(4- isopropoxy- pyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3-yl)- N-methylacetamide 453.1 A D, E 286

2-(3-(5- isopropoxy- pyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-N,N-dimethyl-5- (trifluoromethyl) pyridine-3- sulfonamide 489.1 A D, ED, E 287

N-methyl-N-(5- (trifluoromethyl)- 2-(3-(1,3,3- trimethyl-2-oxo-2,3-dihydro- 1H-pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol-5-ylamino)pyridin-3- yl)acetamide 492.1 A D, E D, E 288

N-(6-(3-(4- isopropoxypyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)-5-methylpyridin- 3-yl)-N- methylacetamide 399.3 A D, E D, E 289

2-(3-(4- isopropylpyridin- 2-yl)- 1,2,4-thiadiazol- 5-ylamino)-(trifluoromethyl) nicotinamide 437.1 D, E D, E 290

N,N-dimethyl-5- (trifluoromethyl)- 2-(3-(1,3,3- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4- thiadiazol-5- ylamino)nicotinamide 478.2 D, E D, E 291

N-methyl-N-(5- (trifluoromethyl)- 2-(3-(1,2,2- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4- thiadiazol-5-ylamino)pyridin- 3-yl)acetamide 478.2 C D, E D, E 292

N,N-dimethyl-5- (trifluoromethyl)- 2-(3-(1,3,3- trimethyl-2-oxo-2,3-dihydro- 1H-pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4- thiadiazol-5-ylamino) nicotinamide 492.2 A D, E D, E 293

N,N-dimethyl-5- (trifluoromethyl)- 2-(3-(1,2,2- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4- thiadiazol-5- ylamino)nicotinamide 478.2 C D, E D, E 294

N-(6-(5-(1- isopropyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1H-1,2,4-triazol- 3-ylamino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 461.3 A D D, E 295

N-(2-(5-(1- isopropyl-2,3- dihydro-1H- pyrro1o[2,3- c]pyridin-5-yl)-1H-1,2,4-triazol- 3-ylamino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 461.3 A D D, E 296

3-(2,2- dimethyl-2,3- dihydrofuro[2,3-c] pyridin-5-yl)-N-(5-isopropyl-4- (trifluoromethyl) pyridin-2-yl)- 1,2,4-thiadiazol-5-amine 436.2 C D D, E D, E 297

N-(6-(3-(5- isopropoxypyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)-5-methylpyridin- 3-yl)-N- methylacetamide 399.1 B D 298

N-(3-(azetidin-1- ylsulfonyl)pyridin- 2-yl)-3-(5- isopropoxypyridin-2-yl)-1,2,4- thiadiazol-5-amine 433.2 B D 299

N-(6-(3-(1- isopropyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4-thiadiazol- 5-ylamino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 478.2 C D D, E D, E 300

N-(6-(3-(5- isopropoxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3-yl)- N-methylacetamide 453.2 A D D D, E301

N-(2-(3-(4- isopropylpyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3-yl)- N-methylacetamide 437.3 C D D, E D, E302

N-(3-(3-(1- isopropyl-1H- pyrrolo[2,3-c] pyridin-5-yl)-1,2,4-thiadiazol-5- ylamino) pyrazin-2-yl)-N- methylacetamide 409.2 C DD, E D, E 303

N2-(3-(1- isopropyl-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol-5- yl)-N3- methylpyrazine- 2,3-diamine 367.2 C D, E 304

N-(2-(3-(1- isopropyl-2,3- dihydro-1H- pyrrolo[3,2- c]pyridin-6-yl)-1,2,4-thiadiazol- 5-ylamino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 478.2 C D D, E D, E 305

5-(3-methyl- pyridin-2- yl)-N-(4- methylpyridin- 2-yl)-1,2,4-thiadiazol- 3-amine 283.8 C D 306

N-methyl-N- (2-(3-(4- (tetrahydro- 2H-pyran-4- yloxy)pyridin-2-yl)-1,2,4- thiadiazol-5- ylamino)-5- (trifluoromethyl) pyridin-3-yl)acetamide 495.3 C D 307

N,N-dimethyl- 2-(3-(1-methyl- 2,3-dihydro- 1H-pyrrolo[2,3- c]pyridin-5-yl)-1,2,4- thiadiazol- 5-ylamino) pyridine-3- sulfonamide 418.2 A D, E308

2-(3-(4-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-N,N-dimethyl- pyridine-3- sulfonamide 421.2 C D, E 309

N-(3-(3-(1- isopropyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4-thiadiazol- 5-ylamino) pyrazin-2-yl)-N- methylacetamide 411.3 C D,E 310

N-(2-(3-(2- isopropyl-2,3- dihydro-1H- pyrrolo[3,4- c]pyridin-6-yl)-1,2,4-thiadiazol- 5-ylamino) pyridin-3-yl)-N- methylacetamide 410.3 A E311

N-(2-(3-(2- isopropyl-2,3- dihydro-1H- pyrrolo[3,4- c]pyridin-6-yl)-1,2,4-thiadiazol- 5-ylamino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 478.2 C D, E 312

1-(2-(3-(5- isopropoxypyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3- yl)pyrrolidin- 2-one 465.1 A D, E 313

N-(3-(3-(5- isopropoxypyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)pyrazin-2-yl)-N- methylacetamide 386.1 A D, E 314

N-(2-(3-(6- isopropoxy- pyridazin-3-yl)- 1,2,4-thiadiazol- 5-ylamino)-5-(trifluoromethyl) pyridin-3-yl)-N- methylacetamide 454.1 A D, E 315

3-(5-isopropoxy- pyrimidin-2-yl)- N-(3-methylpyridin- 2-yl)-1,2,4-thiadiazol-5-amine 329.3 A E 316

N-(2-(3-(5- isopropoxy- pyrimidin-2-yl)- 1,2,4-thiadiazol- 5-ylamino)-5-(trifluoromethyl) pyridin-3-yl)-N- methylacetamide 454.2 A 317

N-(2-(3-(4- isopropoxypyridin- 2-yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3-yl)-N- methylacetamide 453.3 C D, E D, ED, E 318

N-(2-(3-(4- methoxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3-yl)- N-methylacetamide 425.1 C D, E D, ED, E 319

N-(3-((5-(5- isopropoxypyridin- 2-yl)-1,3,4- oxadiazol-2- yl)(methyl)amino)-5- (trifluoromethyl) pyridin-2- yl)acetamide 437.3 A D, E 320

2-(3-(5- isopropoxy-4- (trifluoromethyl) pyridin-2-yl)-1,2,4-thiadiazol- 5-ylamino)- N,N-dimethyl- pyridine-3- sulfonamide489.1 A D, E D, E E 321

2-(3-(5-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-N,N-dimethyl- pyridine-3- sulfonamide 421.2 A D, E D D, E 322

N-(5-isopropyl-4- (trifluoromethyl) pyridin-2-yl)-3- (1-methyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol- 5-amine421.2 C D, E D, E D, E 323

N-(5-isopropyl-3- (trifluoromethyl) pyridin-2-yl)-3- (1-methyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol- 5-amine421.2 C D, E D, E D, E 324

3-(1-methyl-2,3- dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)-N-(3-methyl-5- (trifluoromethyl) pyridin-2-yl)- 1,2,4-thiadiazol- 5-amine393.1 C D D, E D, E 325

N-methyl-N- (2-(3-(pyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3- yl)acetamide 395.2 C D 326

N-methyl-N- (2-(3-(5- (oxetan-3- yloxy)pyridin- 2-yl)-1,2,4-thiadiazol-5- ylamino)pyridin-3- yl)acetamide 399.1 A E 327

isopropyl 2-(3-(5- isopropoxypyridin- 2-yl)-1,2,4- thiadiazol-5-ylamino)nicotinate 400.2 A D D 328

(2-(3-(5-isoprop- oxypyridin-2- yl)-1,2,4- thiadiazol-5- ylamino)-5-(trifluoromethyl) pyridin-3- yl)(pyrrolidin-l- yl)methanone 479.1 A DD, E 329

N-methyl-N- (2-(3-(5- (oxetan-3- yloxy)pyridin- 2-yl)-1,2,4-thiadiazol-5- ylamino)-5- (trifluoromethyl) pyridin-3- yl)acetamide467.1 A D D 330

N-(5-(difluoro- methyl)-2-(3-(1- methyl-2,3- dihydro-1H- pyrrolo[2,3-c]pyridin-5-yl)- 1,2,4- thiadiazol-5- ylamino)pyridin- 3-yl)-N-methylacetamide 432.2 A D D 331

N-methyl-N-(5- (trifluoromethyl)- 6-((3-(1,3,3- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol- 5-yl)amino)-1l2-piperidin-3- yl)acetamide 478.2 332

N-methyl-N-(5- (trifluoromethyl)- 6-((3-(1,2,2- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4- thiadiazol-5- yl)amino)pyridin-3- yl)acetamide 478.2 333

N-methyl-N-(5- (trifluoromethyl)- 6-((3-(1,3,3- trimethyl-2-oxo-2,3-dihydro- 1H-pyrrolo [2,3-c] pyridin-5-yl)- 1,2,4- thiadiazol-5-yl)amino) pyridin-3- yl)acetamide 492.1 334

N-(6-((3-(2,2- dimethyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4-thiadiazol- 5-yl)amino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 464.1 335

N3,N3- dimethyl-5- (trifluoromethyl)- N2-(3-(1,2,2- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)-3H- 1,2l2,4- thiadiazol-5-yl)pyridine- 2,3-diamine 336

5-(5-((3- (dimethyl- amino)-5- (trifluoromethyl) pyridin-2-yl)amino)-1,2,4- thiadiazol-3- yl)-1,3,3- trimethyl-1,3- dihydro-2H-pyrrolo[2,3-c] pyridin-2-one 337

N-(2-((3-(1- isopropyl-3,3- dimethyl-2,3, 3a,6-tetrahydro- 1H-pyrrolo[2,3-c]pyridin- 5-yl)- 1,2,4l2- thiadiazol-5- yl)amino)- 5-(trifluoro-methyl) pyridin-3-yl)- N-methylacetamide 338

N-(6-((3-(1- isopropyl-3,3- dimethyl-2,3, 3a,6-tetrahydro- 1H-pyrrolo[2,3-c]pyridin- 5-yl)- 1,2,4- thiadiazol-5- yl)amino)-5-(trifluoromethyl) pyridin-3-yl)- N-methylacetamide 339

5-(cyclohexyl- oxy)-N-(5-(5- methoxypyridin- 2-yl)-1H-1,2,4-triazol-3-yl) pyridin-2-amine 340

5-(cyclohexyl- oxy)-N-(5-(5- methoxypyridin- 2-yl)-1-methyl- 1H-1,2,4-triazol-3-yl) pyridin-2- amine 341

5-isopropoxy- N-(5-(5- methoxypyridin- 2-yl)-1-methyl- 1H-1,2,4-triazol-3-yl) pyridin-2- amine 342

N-methyl-N-(5- (trifluoromethyl)- 2-((3-(1,2,2- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4- thiadiazol-5-yl)amino)pyridin- 3-yl)acetamide 343

N-(5-(cyclohexyl- oxy)pyridin-2- yl)-5-(5- methoxypyridin- 2-yl)- 1,3,4-oxadiazol-2- amine 344

N-(5-(cyclohexyl- oxy)pyridin-2- yl)-5-(5- methoxypyridin- 2-yl)- 1,3,4-thiadiazol-2- amine 345

N-(3-methyl- pyridin-2- yl)-5-(5- ((tetrahydro-2H- pyran-4-yl)oxy)pyridin- 2-yl)-1,2,4- thiadiazol-3- amine 346

N-methyl-N-(5- (trifluoromethyl)- 6-((5-(1,3,3- trimethyl-2,3,3a,6,7,7a- hexahydro-1H- pyrrolo[2,3- c]pyridin-5-yl)- 1,2,4-thiadiazol-3-yl)amino) pyridin-3- yl)acetamide 347

N-(2-((5-(3,3- dimethyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4-thiadiazol- 3-yl)amino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 348

N-(2-((5-(2,2- dimethyl-2,3- dihydro-1H- pyrrolo[2,3- c]pyridin-5-yl)-1,2,4-thiadiazol- 3-yl)amino)-5- (trifluoromethyl) pyridin-3-yl)-N-methylacetamide 349

N-methyl-N-(5- (trifluoromethyl)- 2-((5-(1,2,2- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol-3-yl)amino)pyridin-3- yl)acetamide 350

N-methyl-N-(5- (trifluoromethyl)- 6-((5-(1,2,2- trimethyl-2,3-dihydro-1H- pyrrolo[2,3-c] pyridin-5-yl)- 1,2,4-thiadiazol-3- yl)amino)pyridin-3- yl)acetamide 351

N-(2-((5-(5- (tert-butoxy)-1,6- dihydropyridin- 2-yl)-1,2,4-thiadiazol-3- yl)amino)-5- (trifluoro- methyl)-2,3- dihydropyridin-3-yl)-N- methylacetamide

A number of references have been cited, the disclosures of each of whichare incorporated herein by reference in their entirety.

1. A compound of Formula (I)

and pharmaceutically acceptable salts, tautomers, isotopologues, orstereoisomers thereof, wherein: W is N or NR; X is N, NR, O, or S; Y isN, NR, O, or S; R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl,each unsubstituted or substituted with one or more substituentsindependently selected from halogen, CN, substituted or unsubstitutedC₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted 3-6 membered heterocyclyl, —NR₂, —COOR, —OR³, —SO₂NR₂,—SO₂(substituted or unsubstituted heterocyclyl), —N(R)CO(R⁴), —CON(R⁵)₂,and substituted or unsubstituted C₆₋₁₀ aryl; R² is

 each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl orsubstituted or unsubstituted C₅₋₆ heteroaryl; Each R³ is independentlyselected from substituted or unsubstituted C₁₋₅ alkyl, or substituted orunsubstituted 3-6 membered heterocyclyl; Each R⁴ is independentlyselected from substituted or unsubstituted C₁₋₅ alkyl, or substituted orunsubstituted C₃₋₆ cycloalkyl; Each R⁵ is independently selected from H,substituted or unsubstituted C₁₋₅ alkyl, substituted or unsubstitutedC₃₋₆ cycloalkyl, and substituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆cycloalkyl), or two R⁵ and the nitrogen to which they are attached forma substituted or unsubstituted 3 to 6 membered heterocyclyl; Each R⁶ isindependently selected from substituted or unsubstituted C₁₋₅ alkyl,substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃ alkyl)(substitutedor unsubstituted C₃₋₆ cycloalkyl), or substituted or unsubstituted 3-8membered heterocyclyl; Each R⁷ is independently selected from H, andsubstituted or unsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen towhich they are attached form a substituted or unsubstituted 3 to 6membered heterocyclyl; R^(N) is H, or substituted or unsubstituted C₁₋₅alkyl; and each R is independently selected from H and substituted orunsubstituted C₁₋₄ alkyl; provided R¹ and R² are not both unsubstituted.2. The compound of claim 1, wherein the compound is a compound offormula (Ia), (Ib), or (Ic)

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof.
 3. The compound of claim 2, wherein X is NR, O,or S, and Y is N.
 4. (canceled)
 5. (canceled)
 6. The compound of claim2, wherein X is N, and Y is NR, O, or S.
 7. (canceled)
 8. (canceled) 9.The compound of claim 2 wherein X is N and Y is N.
 10. The compound ofclaim 1, wherein R¹ is substituted with one or more substituentsindependently selected from halogen, CN, substituted or unsubstitutedC₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted 3-6 membered heterocyclyl, substituted or unsubstitutedC₆₋₁₀ aryl, —NR₂, —COOR, —OR³, —SO₂NR₂, —SO₂(substituted orunsubstituted heterocyclyl), —N(R)CO(R⁴), and —CON(R⁵)₂.
 11. Thecompound of claim 1, wherein R¹ is substituted with one or moresubstituents independently selected from Cl, F, Br, CN, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂,—C(CH₃)₃, —CH₂F, —CHF₂, —CF₃; substituted or unsubstituted cycloalkylselected from cyclopropyl, cyclobutyl, and cyclopentyl; substituted orunsubstituted heterocyclyl selected from pyrrolidyl, pyrrolidinonyl,piperidyl, piperazinyl, and morpholinyl; substituted or unsubstitutedphenyl; —NH₂, —NHCH₃, —N(CH₃)₂, —COOH, —COOCH₃, —OR³, —SO₂N(CH₃)₂;—SO₂(aziridinyl), —NHCO(R⁴), —N(CH₃)CO(R⁴), —N(CH₂CH₃)CO(R⁴),—N(CH₂CH₂CH₃)CO(R⁴), —N(CH₂CH(CH₃)₂)CO(R⁴), and —CON(R⁵)₂.
 12. Thecompound of claim 1, wherein R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl, or1-CH₃-piperidyl.
 13. The compound of claim 1, wherein R³ is —CH₃,—CH(CH₃)₂, cyclohexyl, tetrahydropyranyl, piperidyl, or 1-CH₃-piperidyl.14. The compound of claim 1, wherein R⁴ is selected from —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂; substituted or unsubstituted cycloalkyl selectedfrom cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
 15. Thecompound of claim 1, wherein R⁴ is selected from —CH₃, —CH₂CH(CH₃)₂,cyclopropyl, cyclobutyl, or cyclopentyl.
 16. The compound of claim 1,wherein each R⁵ is independently selected from H, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂; substituted or unsubstituted cycloalkyl selectedfrom cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; substituted orunsubstituted (alkyl)-(cycloalkyl) selected from —CH₂-cyclopropyl,—CH₂-cyclobutyl, and —CH₂-cyclopentyl; or two R⁵ and the nitrogen towhich they are attached form a pyrrolidyl.
 17. The compound of claim 1,wherein each R⁵ is independently selected from H, —CH₃, cyclopropyl,cyclobutyl, cyclobutyl substituted with one or more F, and—CH₂-cyclopropyl; or two R⁵ and the nitrogen to which they are attachedform a pyrrolidyl.
 18. The compound of claim 1, wherein R¹ is 2-pyridyl,3-pyridyl or pyrazinyl.
 19. The compound of claim 1, wherein R² issubstituted with one or more substituents Z, wherein Z is independentlyselected from halogen, CN, substituted or unsubstituted C₁₋₄ alkyl,substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted 3-6 membered heterocyclyl, —NR(substituted orunsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂, or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl orsubstituted or unsubstituted C₅₋₆ heteroaryl.
 20. The compound of claim1, wherein R² is substituted with one or more substituents independentlyselected from Cl, F, Br, CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂,—CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F, —CHF₂, —CF₃; substitutedor unsubstituted cycloalkyl selected from cyclopropyl, cyclobutyl, andcyclopentyl; substituted or unsubstituted heterocyclyl selected frompiperidyl, piperazinyl, morpholinyl and thiomorpholinyl;—NH(bicyclo[1.1.1]pentyl), —N(CH₃)(bicyclo[1.1.1]pentyl); —NHCO(CH₃),—N(CH₃)CO(CH₃), —NHCO(CH₂CH₃), —N(CH₃)CO(CH₂CH₃); —COOH, —COOCH₃;—SO₂CH₃, —SO₂CH₂CH₃; —SO₂NHCH₃, —SO₂N(CH₃)₂; —SO₂(aziridinyl),—SO₂(piperidyl), —SO₂(1-methyl-aziridinyl), —SO₂(1-methyl-piperidyl),SO₂(1-cyclopropyl-piperidyl), —OR⁶, and —CON(R⁷)₂.
 21. The compound ofclaim 1, wherein R⁶ is selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, difluorocyclobutyl, difluorocyclopentyl,—CH₂-cyclopropyl, —CH₂-cyclobutyl, oxetanyl, piperidyl, fluoropiperidyl,-(1-methyl-piperidyl), -(1-isopropyl-piperidyl),-(1-isopropyl-fluoropiperidyl), -(1-isopropyl-difluoropiperidyl),-(1-cyclopropyl-piperidyl), -(1-cyclobutyl-piperidyl),-(1-cyclopentyl-piperidyl), -(1-cyclopropyl-fluoropiperidyl),-(1-cyclopropyl-difluoropiperidyl), -(1-CH₂-cyclopropyl-piperidyl),-(1-acetyl-piperidyl), -(1-(COCH(CH₃)₂)-piperidyl), tetrahydrofuranyl,tetrahydropyranyl, -(2-methyl-2-azaspiro[3.3]heptyl),-(2-cyclopropyl-2-azaspiro[3.3]heptyl), and-(6-methyl-6-azaspiro[3.4]octyl).
 22. The compound of claim 1, whereinR⁶ is selected from —CH₃, —CH(CH₃)₂, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CHF₂,—CF₃, —CH₂CF₃, cyclopropyl, cyclohexyl, difluorocyclobutyl,—CH₂-cyclopropyl, oxetanyl, piperidyl, -(1-methyl-piperidyl),-(1-isopropyl-difluoropiperidyl), -(1-cyclopentyl-piperidyl),-(1-cyclopropyl-fluoropiperidyl), -(1-cyclopropyl-difluoropiperidyl),-(1-CH₂-cyclopropyl-piperidyl), -(1-acetyl-piperidyl),-(1-(COCH(CH₃)₂)-piperidyl), tetrahydropyranyl,-(2-methyl-2-azaspiro[3.3]heptyl),-(2-cyclopropyl-2-azaspiro[3.3]heptyl), and-(6-methyl-6-azaspiro[3.4]octyl).
 23. The compound of claim 1, whereineach R⁷ is independently selected from —H, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃, or two R⁷ and the nitrogen towhich they are attached form a heterocycle selected from unsubstitutedor substituted pyrrolidyl, piperidyl, piperazinyl, or morpholinyl. 24.The compound of claim 1, wherein each R⁷ is independently selected from—H, —CH₃, and —CH₂CF₃, or two R⁷ and the nitrogen to which they areattached form a pyrrolidyl, 1-methyl-piperazinyl, or morpholinyl. 25.The compound of claim 1, wherein R² is 2-pyridyl substituted with twosubstituents Z, wherein the two Z together with the carbons to whichthey are attached form a substituted or unsubstituted 5-memberedheterocyclyl.
 26. The compound of claim 1, wherein R² is 2-pyridylsubstituted with two substituents Z, wherein the two Z together with thecarbons to which they are attached form a substituted or unsubstituted5-membered heteroaryl.
 27. The compound of claim 25, wherein the two Ztogether with the carbons to which they are attached form a substitutedor unsubstituted dihydropyrrolyl or dihydrofuryl.
 28. The compound ofclaim 27, wherein R² is a substituted or unsubstituted6,7-dihydro-5H-pyrrolo[3,4-b]pyridyl;2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl;2,3-dihydro-1H-pyrrolo[3,4-c]pyridyl;2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl; or2,3-dihydrofuro[2,3-c]pyridyl.
 29. The compound of claim 25, wherein theheterocyclyl is substituted with one or more substituents selected from—CH₃, —CH(CH₃)₂, —CH₂-cyclopropyl, and —COCH₃.
 30. The compound of claim26, wherein R² is 2-pyridyl substituted with two substituents Z, whereinthe two Z together with the carbons to which they are attached form asubstituted pyrrolyl.
 31. The compound of claim 30, wherein R² is asubstituted or unsubstituted 1H-pyrrolo[2,3-c]pyridyl.
 32. (canceled)33. (canceled)
 34. (canceled)
 35. The compound of claim 1, wherein thecompound is selected from Table
 1. 36. A compound of formula (II)

and pharmaceutically acceptable salts, tautomers, isotopologues, orstereoisomers thereof, wherein: W is N, NR, or S; X is N, NR, O, or S; Yis N, NR, O, or S; R¹ is 2-pyridyl, 3-pyridyl, pyrazinyl, or pyrimidyl,each unsubstituted or substituted with one or more substituentsindependently selected from halogen, CN, substituted or unsubstitutedC₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl, substituted orunsubstituted 3-6 membered heterocyclyl, —NR₂, —COOR, —OR³, —SO₂NR₂,—SO₂(substituted or unsubstituted heterocyclyl), —N(R)CO(R⁴), —CON(R⁵)₂,and substituted or unsubstituted C₆₋₁₀ aryl; R² is

 each unsubstituted or substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂; or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl orsubstituted or unsubstituted C₅₋₆ heteroaryl; Each R³ is independentlyselected from substituted or unsubstituted C₁₋₅ alkyl, or substituted orunsubstituted 3-6 membered heterocyclyl; Each R⁴ is independentlyselected from substituted or unsubstituted C₁₋₅ alkyl, or substituted orunsubstituted C₃₋₆ cycloalkyl; Each R⁵ is independently selected from H,substituted or unsubstituted C₁₋₅ alkyl, substituted or unsubstitutedC₃₋₆ cycloalkyl, and substituted or unsubstituted (C₁₋₃ alkyl)(C₃₋₆cycloalkyl), or two R⁵ and the nitrogen to which they are attached forma substituted or unsubstituted 3 to 6 membered heterocyclyl; Each R⁶ isindependently selected from substituted or unsubstituted C₁₋₅ alkyl,substituted or unsubstituted C₃₋₆ cycloalkyl, —(C₁₋₃ alkyl)(substitutedor unsubstituted C₃₋₆ cycloalkyl), or substituted or unsubstituted 3-8membered heterocyclyl; Each R⁷ is independently selected from H, andsubstituted or unsubstituted C₁₋₅ alkyl, or two R⁵ and the nitrogen towhich they are attached form a substituted or unsubstituted 3 to 6membered heterocyclyl; R^(N) is H, or substituted or unsubstituted C₁₋₅alkyl; and each R is independently selected from H and substituted orunsubstituted C₁₋₄ alkyl; provided R¹ and R² are not both unsubstituted.37. The compound of claim 36, wherein the compound is a compound offormula (IIa)

and pharmaceutically acceptable salts, tautomers, isotopologues, andstereoisomers thereof.
 38. The compound of claim 37, wherein Y is N. 39.The compound of claim 36, wherein R¹ is substituted with one or moresubstituents independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, substituted orunsubstituted C₆₋₁₀ aryl, —NR₂, —COOR, —OR³, —SO₂NR₂, —SO₂(substitutedor unsubstituted heterocyclyl), —N(R)CO(R⁴), and —CON(R⁵)₂.
 40. Thecompound of claim 36, wherein R¹ is substituted with one or moresubstituents independently selected from Cl, F, Br, CN, —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂,—C(CH₃)₃, —CH₂F, —CHF₂, —CF₃; substituted or unsubstituted cycloalkylselected from cyclopropyl, cyclobutyl, and cyclopentyl; substituted orunsubstituted heterocyclyl selected from pyrrolidyl, pyrrolidinonyl,piperidyl, piperazinyl, and morpholinyl; substituted or unsubstitutedphenyl; —NH₂, —NHCH₃, —N(CH₃)₂, —COOH, —COOCH₃, —OR³, —SO₂N(CH₃)₂;—SO₂(aziridinyl), —NHCO(R⁴), —N(CH₃)CO(R⁴), —N(CH₂CH₃)CO(R⁴),—N(CH₂CH₂CH₃)CO(R⁴), —N(CH₂CH(CH₃)₂)CO(R⁴), and —CON(R⁵)₂.
 41. Thecompound of claim 36, wherein R³ is —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, piperidyl,or 1-(CH₃)-piperidyl.
 42. The compound of claim 36, wherein R⁴ isselected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃, —CH(CH₃)₂; substituted orunsubstituted cycloalkyl selected from cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl.
 43. The compound of claim 36, wherein eachR⁵ is independently selected from H, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂; substituted or unsubstituted cycloalkyl selected fromcyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; substituted orunsubstituted (alkyl)-(cycloalkyl) selected from —CH₂-cyclopropyl,—CH₂-cyclobutyl, and —CH₂-cyclopentyl; or two R⁵ and the nitrogen towhich they are attached form a pyrrolidyl.
 44. The compound of claim 36,wherein R¹ is 2-pyridyl, 3-pyridyl or pyrazinyl.
 45. The compound ofclaim 36, wherein R² is substituted with one or more substituents Z,wherein Z is independently selected from halogen, CN, substituted orunsubstituted C₁₋₄ alkyl, substituted or unsubstituted C₃₋₇ cycloalkyl,substituted or unsubstituted 3-6 membered heterocyclyl, —NR(substitutedor unsubstituted C₃₋₇ cycloalkyl), —N(R)COR, —COOR, —SO₂(C₁₋₃ alkyl),—SO₂NR₂, —SO₂(substituted or unsubstituted heterocyclyl), —OR⁶, and—CON(R⁷)₂, or two Z together with the carbons to which they are attachedform a substituted or unsubstituted 5-6 membered heterocyclyl orsubstituted or unsubstituted C₅₋₆ heteroaryl.
 46. The compound of claim36, wherein R² is substituted with one or more substituentsindependently selected from Cl, F, Br, CN, —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F, —CHF₂, —CF₃;substituted or unsubstituted cycloalkyl selected from cyclopropyl,cyclobutyl, and cyclopentyl; substituted or unsubstituted heterocyclylselected from piperidyl, piperazinyl, morpholinyl and thiomorpholinyl;—NH(bicyclo[1.1.1]pentyl), —N(CH₃)(bicyclo[1.1.1]pentyl); —NHCO(CH₃),—N(CH₃)CO(CH₃), —NHCO(CH₂CH₃), —N(CH₃)CO(CH₂CH₃); —COOH, —COOCH₃;—SO₂CH₃, —SO₂CH₂CH₃; —SO₂NHCH₃, —SO₂N(CH₃)₂; —SO₂(aziridinyl),—SO₂(piperidyl), —SO₂(1-methyl-aziridinyl), —SO₂(1-methyl-piperidyl),SO₂(1-cyclopropyl-piperidyl), —OR⁶, and —CON(R⁷)₂.
 47. The compound ofclaim 36, wherein R⁶ is selected from —CH₃, —CH₂CH₃, —CH₂CH₂CH₃,—CH(CH₃)CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —C(CH₃)₃, —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂, —CH₂CF₃, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, difluorocyclobutyl, difluorocyclopentyl,—CH₂-cyclopropyl, —CH₂-cyclobutyl, oxetanyl, piperidyl, fluoropiperidyl,-(1-methyl-piperidyl), -(1-isopropyl-piperidyl),-(1-isopropyl-fluoropiperidyl), -(1-isopropyl-difluoropiperidyl),-(1-cyclopropyl-piperidyl), -(1-cyclobutyl-piperidyl),-(1-cyclopentyl-piperidyl), -(1-cyclopropyl-fluoropiperidyl),-(1-cyclopropyl-difluoropiperidyl), -(1-CH₂-cyclopropyl-piperidyl),-(1-acetyl-piperidyl), -(1-(COCH(CH₃)₂)-piperidyl), tetrahydrofuranyl,tetrahydropyranyl, -(2-methyl-2-azaspiro[3.3]heptyl),-(2-cyclopropyl-2-azaspiro[3.3]heptyl), and-(6-methyl-6-azaspiro[3.4]octyl).
 48. The compound of claim 36, whereineach R⁷ is independently selected from —H, —CH₃, —CH₂CH₃, —CH₂F, —CHF₂,—CF₃, —CH₂CH₂F, —CH₂CHF₂, and —CH₂CF₃, or two R⁷ and the nitrogen towhich they are attached form a heterocycle selected from unsubstitutedor substituted pyrrolidyl, piperidyl, piperazinyl, or morpholinyl. 49.The compound of claim 36, wherein R² is 2-pyridyl substituted with twosubstituents Z, wherein the two Z together with the carbons to whichthey are attached form a substituted or unsubstituted 5-memberedheterocyclyl.
 50. The compound of claim 49, wherein the two Z togetherwith the carbons to which they are attached form a substituted orunsubstituted dihydropyrrolyl or dihydrofuryl.
 51. The compound of claim50, wherein R² is a substituted or unsubstituted6,7-dihydro-5H-pyrrolo[3,4-b]pyridyl;2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl;2,3-dihydro-1H-pyrrolo[3,4-c]pyridyl;2-oxo-2,3-dihydro-1H-pyrrolo[2,3-c]pyridyl; or2,3-dihydrofuro[2,3-c]pyridyl.
 52. (canceled)
 53. (canceled)
 54. Thecompound of claim 36, wherein the compound is selected from Table
 1. 55.A pharmaceutical composition comprising an effective amount of acompound of claim 1 or a pharmaceutically acceptable salt, tautomer,isotopologue, or stereoisomer thereof, and a pharmaceutically acceptablecarrier, excipient or vehicle.
 56. A method of killing a filarial worm,comprising contacting the filarial worm with a compound of claim 1, or apharmaceutical composition of claim 55, or a pharmaceutically acceptablesalt, tautomer, isotopologue, or stereoisomer thereof, in an amounteffective to kill the filarial worm.
 57. A method of inhibiting growthor molt of a filarial worm, comprising contacting the filarial worm witha compound of claim 1, or a pharmaceutical composition of claim 55, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, in an amount effective to inhibit growth or moltof the filarial worm.
 58. A method of inhibiting motility of a filarialworm, comprising contacting the filarial worm with a compound of claim1, or a pharmaceutical composition of claim 55, or a pharmaceuticallyacceptable salt, tautomer, isotopologue, or stereoisomer thereof, in anamount effective to inhibit motility of the filarial worm.
 59. A methodfor the treatment or prevention of helminthic infections and diseases,the methods comprising administering to a subject an effective amount ofa compound of claim 1, or a pharmaceutical composition of claim 55, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof.
 60. The method of claim 59, wherein the helminthicinfection is a filarial worm infection.
 61. A method for the treatmentor prevention of helminthic infections and diseases, the methodscomprising administering to a subject an effective amount of a compoundof claim 1, or a pharmaceutical composition of claim 55, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof in combination with another anti-parasitic agent.62. The method of claim 61, wherein the helminthic infection is afilarial worm infection.
 63. The method of claim 61, wherein theanti-parasitic agent is selected from flubendazole, albendazole,mebendazole, thiabendazole, fenbendazole, triclabendazole, ivermectin,abamectin, diethylcarbamazine (DEC), suramin, pyrantel pamoate,levamisole, niclosamide, nitazoxanide, oxyclozanide, praziquantel,emodepside, monepantel, derquantel, oxfendazole, or pelletierinesulphate.
 64. The method of claim 61, wherein the anti-parasitic agentis a Wolbachia targeting agent.
 65. The method of claim 64, wherein theWolbachia targeting agent is doxycycline.
 66. The method of claim 61,wherein the anti-parasitic agent is selected from ivermectin, moxidectinor selamectin.
 67. A pharmaceutical composition comprising an effectiveamount of a compound of claim 36 or a pharmaceutically acceptable salt,tautomer, isotopologue, or stereoisomer thereof, and a pharmaceuticallyacceptable carrier, excipient or vehicle.
 68. A method of killing afilarial worm, comprising contacting the filarial worm with a compoundof claim 36, or a pharmaceutical composition of claim 67, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof, in an amount effective to kill the filarial worm.69. A method of inhibiting growth or molt of a filarial worm, comprisingcontacting the filarial worm with a compound of claim 36, or apharmaceutical composition of claim 67, or a pharmaceutically acceptablesalt, tautomer, isotopologue, or stereoisomer thereof, in an amounteffective to inhibit growth or molt of the filarial worm.
 70. A methodof inhibiting motility of a filarial worm, comprising contacting thefilarial worm with a compound of claim 36, or a pharmaceuticalcomposition of claim 67, or a pharmaceutically acceptable salt,tautomer, isotopologue, or stereoisomer thereof, in an amount effectiveto inhibit motility of the filarial worm.
 71. A method for the treatmentor prevention of helminthic infections and diseases, the methodscomprising administering to a subject an effective amount of a compoundof claim 36, or a pharmaceutical composition of claim 67, or apharmaceutically acceptable salt, tautomer, isotopologue, orstereoisomer thereof.
 72. A method for the treatment or prevention ofhelminthic infections and diseases, the methods comprising administeringto a subject an effective amount of a compound of claim 36, or apharmaceutical composition of claim 67, or a pharmaceutically acceptablesalt, tautomer, isotopologue, or stereoisomer thereof in combinationwith another anti-parasitic agent.